Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2020 / Article
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Endothelium and Platelets as a Common Ground for Oxidative Stress Induced Alterations in Thrombosis, Haemostasis, and Inflammation in Acute and Chronical Diseases

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Review Article | Open Access

Volume 2020 |Article ID 1496462 | https://doi.org/10.1155/2020/1496462

Andy W. C. Man, Huige Li, Ning Xia, "Impact of Lifestyles (Diet and Exercise) on Vascular Health: Oxidative Stress and Endothelial Function", Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 1496462, 22 pages, 2020. https://doi.org/10.1155/2020/1496462

Impact of Lifestyles (Diet and Exercise) on Vascular Health: Oxidative Stress and Endothelial Function

Academic Editor: Edyta Sutkowska
Received26 Jun 2020
Revised25 Aug 2020
Accepted28 Aug 2020
Published26 Sep 2020

Abstract

Healthy lifestyle and diet are associated with significant reduction in risk of obesity, type 2 diabetes, and cardiovascular diseases. Oxidative stress and the imbalance between prooxidants and antioxidants are linked to cardiovascular and metabolic diseases. Changes in antioxidant capacity of the body may lead to oxidative stress and vascular dysfunction. Diet is an important source of antioxidants, while exercise offers many health benefits as well. Recent findings have evidenced that diet and physical factors are correlated to oxidative stress. Diet and physical factors have debatable roles in modulating oxidative stress and effects on the endothelium. Since endothelium and oxidative stress play critical roles in cardiovascular and metabolic diseases, dietary and physical factors could have significant implications on prevention of the diseases. This review is aimed at summarizing the current knowledge on the impact of diet manipulation and physical factors on endothelium and oxidative stress, focusing on cardiovascular and metabolic diseases. We discuss the friend-and-foe role of dietary modification (including different diet styles, calorie restriction, and nutrient supplementation) on endothelium and oxidative stress, as well as the potential benefits and concerns of physical activity and exercise on endothelium and oxidative stress. A fine balance between oxidative stress and antioxidants is important for normal functions in the cells and interfering with this balance may lead to unfavorable effects. Further studies are needed to identify the best diet composition and exercise intensity.

1. Introduction

Obesity has become an epidemic and represents the major risk factor for several chronic diseases, including diabetes, cardiovascular diseases, and cancer [1]. Dietary modifications and physical exercise are popular among individuals who want to prevent overweight and keep fit. However, some recent studies have also suggested that the enthusiasm for the potential benefits of specific diets may exceed the current evidence supporting their implications [2, 3]. Therefore, it is very important to reappraise the risks and benefits of different diets to avoid unnecessary side effects.

The imbalance between prooxidants and antioxidants is linked to cardiovascular and metabolic diseases [4]. In normal conditions, homeostatic reactive oxygen species (ROS) act as secondary messengers in various intracellular signaling pathways in the cardiovascular system [5]. However, cellular oxidative stress is developed when the production of ROS and other oxidants exceeds the antioxidant defense [6]. Oxidative stress may lead to the subsequence oxidative modification or damage lipids, proteins, and DNA with deleterious consequences for metabolic and cardiovascular diseases [5]. Indeed, it has been shown that dietary and physical factors play an important role in modulation oxidative stress and endothelial function. Diet is a very important source of antioxidants, while exercising offers many health benefits, especially to cardiovascular system and muscle. Recent studies and media have suggested some specific diets to prevent overweight and improve cardiovascular health, including Mediterranean diet, ketogenic diet, and calorie restrictions [79]. However, different diets and physical factors have debatable roles in modulating oxidative stress and effects on the vascular system. The knowledge about the role of the behaviors and factors which are protective or harmful to the endothelium is still growing, and the newest information is recently summarized [10]. Since the endothelium and oxidative stress play critical roles in cardiovascular and metabolic diseases, appropriate choice of dietary and physical factors could have significant implications in the prevention of cardiovascular and metabolic diseases.

In this review, we summarize current knowledge on the impact of diet modification (including different diet styles, calorie restriction, and nutrient supplementation) and physical factors on endothelium and oxidative stress. Besides, we further discuss the friend-and-foe roles of dietary on endothelium and oxidative stress, focusing on cardiovascular and metabolic diseases.

2. Endothelium

Endothelium is a single layer of flat, polygonal endothelial cells that rest on the inner walls of blood vessels. Endothelium plays an important role in modulating vascular function by sensing the shear or frictional force between blood flow and vascular endothelium. Upon stimuli, such as blood flow and receptor-mediated stimulants, endothelial cells release important vasoactive substances including both vasodilating [such as endothelium-derived hyperpolarizing factors (EDHFs), prostacyclin (PGI2), and nitric oxide (NO)] and vasoconstricting factors [such as endothelin-1 (ET-1), thromboxane A2 (TXA2), and angiotensin II (Ang II)] to regulate vascular tone and architectures [1113]. The activity of endothelial-derived NO or endothelium-derived relaxing factor (EDRF) plays an important role in the regulation of vascular function, blood pressure, and blood flow and has been widely used as a clinical marker of endothelial function [14, 15]. Mechanical forces elicited by the blood flow (shear stress) and pressure (cyclic strain) stimulate the gene expressions in endothelial cells and activate endothelial nitric oxide synthase (eNOS), which produces NO to regulate vascular function [16, 17]. In addition, it is known that laminar shear stress can also regulate antioxidant enzymes [18].

Vascular endothelium is the primary site of dysfunction in metabolic and cardiovascular diseases. Moreover, endothelial dysfunction is a hallmark of vascular aging [19]. Risk factors including hypertension, hypercholesterolemia, diabetes, and smoking are all associated with endothelial dysfunction [20]. Endothelial dysfunction is mainly characterized by the impairment in endothelium-dependent relaxation of blood vessels and the induction of a proinflammatory or prothrombotic state [16]. While NO inhibits platelet aggregation, smooth muscle cell proliferation, and the adhesion of monocytes to endothelial cells, depletion of NO leads to endothelial dysfunction and abnormal vascular remodeling [21]. Apart from pathological conditions, the anticontractile ability of endothelium is also significantly reduced during aging [19, 22], partly due to the decreased eNOS expression, NO bioavailability, or the soluble guanylyl cyclase (sGC) presence in the endothelium of aged arteries [23, 24]. Several pharmacological strategies including statins, angiotensin II receptor antagonists, and angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to improve endothelial function in different studies [25]. Nonpharmacological interventions, such as physical activity and nutritional factors also play an important role in maintaining normal endothelial function [10].

3. Oxidative Stress in the Endothelium

Oxidative stress occurs when the cellular production of oxidant molecules, such as ROS, exceeds antioxidants’ ability to defeat these insults. Generation of ROS is a normal physiological process in aerobic organisms. Vascular ROS are important intracellular signaling messengers that regulate vascular contractility, cell growth, and vascular remodeling [26]; however, oxidative stress can trigger the pathogenesis of related cardiovascular diseases [27]. Under normal conditions, deleterious ROS are mostly removed by cellular antioxidant systems (Figure 1). Excessive ROS are known to cause lipid peroxidation and oxidative modifications of proteins and nucleic acids that cause endothelial dysfunction [28].

Oxidative stress and the associated oxidative damage are mediators of vascular injury and inflammation in many cardiovascular diseases, especially when complicated with hypertension, hyperlipidemia, and diabetes [29, 30]. The major source of oxidative stress in the arterial wall is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) [31], which is implicated in the generation of ROS and the scavenging of NO [32]. In endothelium, increased generation of ROS reduces NO bioavailability, resulting in promotion of vasoconstriction and endothelial dysfunction. Other sources of ROS in the vascular wall include mitochondrial respiratory chain and other enzymatic reactions such as cyclooxygenase (COX), xanthine oxidase (XO), lipooxygenase (LOX), cytochrome P450, and dysfunctional eNOS [3335]. On the other hand, vascular wall contains various enzymes that can reduce the ROS burden and act as antioxidant defense systems. These include superoxidase dismutase (SOD), catalase, glutathione peroxidase (GPx), heme oxygenase (HO), thioredoxin peroxidase (TPX), and paraoxonase (PON) [33, 36, 37]. Oxidative stress can lead to the oxidation of low-density lipoprotein (LDL), which inhibits the release of EDRF more than native or unoxidized LDL [14]. Moreover, oxidized LDL (ox-LDL) is cytotoxic to endothelial cells and chemotactic for monocytes, leading to accumulation of inflammatory cells and ROS in vasculature [38, 39]. Since vascular oxidative stress is the main pathophysiological mechanism leading to blunt NO bioavailability and endothelial dysfunction, attentions to potential treatment or prevention by dietary antioxidant substances have been drawn.

4. Diet Effect on Endothelial Function and Oxidative Stress

Healthy lifestyle and diet are associated with significant reduction in risk of obesity, type 2 diabetes, and cardiovascular diseases [4042]. Due to the important role of ROS in CVD as mentioned above, there has been enormous interest in the application of naturally occurring antioxidants and diet interventions to ease or prevent metabolic and cardiovascular diseases.

It has been demonstrated that dietary factors may induce significant changes on vascular reactivity [15, 4345]. Epidemiological evidence supports the concept that diets rich in fruits and vegetables promote health and prevent the development of cardiovascular diseases [46, 47]. A variety of nutrients have shown to improve endothelial function and prevent cardiovascular diseases. Recently, attention has been focused on dietary patterns in populations with lower prevalence of cardiovascular disease, for example, Mediterranean diet. A longitudinal investigation on human subjects suggests that a healthy diet containing more lean fish, raw vegetables, and fewer high-fat dairy products is associated with less endothelial dysfunction [48]. In addition, consumption of plant-derived foods which contain micronutrients, such as fiber, antioxidant, and phytochemicals, may inhibit intracellular inflammatory signaling pathways and reduce oxidative stress [49]. Here, we summarize the recent results from the animal studies and randomized trials on diet interventions and supplements that modulate vascular functions and discuss on both their beneficial and side effects.

4.1. High-Fat Diet

According to American Heart Association (AHA) guidelines, diet with more than 35% of total calories from fat is regarded as high-fat diet (HFD) [50]. HFD is a common experimental diet model used to induce obesity in animals. In general, there is no doubt that HFD is associated with an increased risk of cardiovascular diseases. Early researches, working on HFD and cardiovascular risk, focused on metabolic and lipid profile abnormalities [51], while more recent studies have indicated a potential and direct effect of endothelial dysfunction induced by dietary fat intake [52, 53]. HFD is considered as a risk factor for cardiovascular disease and causes endothelial dysfunction mostly due to its association with obesity and insulin resistance [54, 55]. Indeed, single high-fat meal can already impair endothelial function transiently, in terms of flow-dependent vasoactivity in normocholesterolemic volunteers [56]. Two consecutive fat-rich meals can impair endothelial function and elevate oxidative stress markers in healthy man [57]. Four-day HFD intake can induce endothelium-dependent vasodilator dysfunction associated with diminished NO bioavailability in healthy adults [53]. These suggest that HFD could have a direct negative effect on endothelium. Nevertheless, HFD can impair endothelial function in mice and reduce the local antioxidant defense in aorta [58]. HFD may induce endothelial dysfunction, at least partly, due to triacylglycerols that reduce NO bioavailability and increase oxidative stress [52, 57].

Indeed, not all HFDs have negative effects on endothelial function, but rather depend on different types of fat [59]. High intake of saturated fat increases the risk of cardiovascular diseases and decreases endothelial fibrinolytic capacity [60]. Diet high in saturated fat has been shown to induce cholesterol-independent endothelial dysfunction and increase markers of oxidative stress in rat [61]. The habitual consumption of diet high in saturated fat is strongly associated with impaired endothelial function (reactive hyperaemia index) in young overweight adults [62]. On the other hand, diets enriched in unsaturated fatty acids seem to show beneficial effects on endothelial function [63]. Obesity induced by high unsaturated-fat diet in rat has improved vascular reactivity to leptin and does not generate endothelial dysfunction, possibly due to the increase of vascular sensitivity to leptin and leptin-induced NO bioavailability [64]. In addition, high intake of trans fatty acids can adversely affect endothelial function and increase plasma inflammatory marker including C-reactive protein (CRP), interleukin-6 (IL-6), and soluble cell adhesion molecules (sICAM-1 and sVCAM-1) according to a cross-sectional study of 730 women [65]. High trans-fat diet has also been shown to reduce endothelial function (flow-mediated dilation) [66, 67] as well as endothelial cell activation [65]. Trans-fat may cause endothelial dysfunction, at least partially, by increasing NF-κB activation and impair insulin-mediated NO production in endothelial cells [68].

While HFD is relatively an experimental diet, cafeteria diet (CAF) containing a variety of highly palatable, high-salt, high-fat, and low-fiber energy dense foods, which is accessible in Western societies, is more accurately reflecting an obese diet [69]. CAF is a robust model of human metabolic syndrome with liver and adipose inflammation [70]. Indeed, both HFD and CAF can induce obesity, glucose intolerance, and insulin resistance to a comparable extent [71]. CAF can induce endothelial dysfunction in the absence of insulin resistance in rats [72], as well as vascular contractile dysfunction associated with increased oxidative stress and morphological remodeling in a hamster model [73]. In addition, CAF is more effective than HFD in causing PVAT-induced vascular dysfunction, associated with a significant reduction of vasodilatory response to acetylcholine in both mice [71] and rat [72]. Therefore, diet consisting of high fat, especially trans-fat and saturated fat can cause endothelial dysfunction and significantly increase the risk of cardiovascular diseases.

4.2. High-Sugar Diet

There is consensus that overconsumption of added sugar foods is positively associated with the risk for obesity and cardiovascular diseases [74, 75]. A prospective study has shown that people who got 17% to 21% of their calories from added sugar had a 38% higher risk of dying from cardiovascular disease compared with those who consumed 8% of their calories as added sugar [74]. Indeed, sugar added to foods and drinks supplies considerable extra calories without any benefits and may compromise the attainment of adequate dietary vitamin and mineral intake from the diet.

The new paradigm views overconsumption of sugar as an independent risk factor in cardiovascular diseases and other metabolic diseases [75]. High sugar intake may also cause endothelial dysfunction. Indeed, high glucose level promotes ROS formation, oxidative stress, and cellular death [76, 77]. Acute hyperglycemia caused by high glucose ingestion acutely deteriorates endothelial function in both human and animal studies, attributed by hyperglycemia-induced oxidative stress [7881]. Exposure to high glucose increases eNOS activity and causing ROS formation due to eNOS uncoupling and aldose reductase activation in endothelial cells [82]. On the other hand, a recent double-blind randomized crossover trial has demonstrated that fructose load in healthy young subjects leads to unfavorable modifications of metabolic parameters, increased systolic blood pressure, and decreased endothelial NO production comparing to the same amount of glucose [83].

Another possible mechanism of how high-sugar diet induces endothelial dysfunction is attributed by advanced glycation end products (AGEs), a group of modified proteins and/or lipids that become glycated after exposure to sugars. AGEs can be ingested with high-temperature processed foods and also endogenously formed by nonenzymatic glycoxidation as a consequence of a high dietary sugar intake [84]. Chronic hyperglycemia promotes the formation of AGEs [85, 86], which have significant proinflammatory and prooxidant effects that contribute towards the pathology of diabetic and aging-related complications [87, 88]. In diabetic patients, high-AGE diet causes a significant increase in serum inflammatory markers [CRP and tumor necrosis factor α (TNF-α)] and endothelial dysfunction marker VCAM-1, whereas a low-AGE diet leads to a suppression of all these markers [89].

Another interesting mechanism by which high-sugar diet could promote oxidative stress is via protein phosphatase 2A (PP2A), a serine/threonine phosphatase that is responsible for the dephosphorylation of a wide range of substrates involved in cellular signaling, including p66Shc. High level of sugar has been shown to activate PP2A and NF-κB [90, 91]. P66shc is a longevity protein that regulates ROS and apoptosis, while dephosphorylated p66Shc may translocate into mitochondria and trigger oxidative stress [92]. Conversely, inhibition of high glucose-mediated PP2A expression prevents oxidative stress and increases NO production, thus reducing endothelial dysfunction [90].

4.3. Ketogenic Diet/Low-Carbohydrate, High-Fat Diet

The ketogenic diet is a low-carbohydrate, high-fat and adequate protein diet described a few decades ago for the management of children with epilepsy [93]. A classic ketogenic diet consists of a ratio of 4 : 1 fat to carbohydrate and protein [94]. In recent years, ketogenic diet or low-carbohydrate, high-fat diet (LCHFD) is suggested to be a successful weight-loss tool for obese subjects [95, 96] and popular among healthy people to maintain bodyweight. The rationale behind this diet is to induce ketosis, which the shift to fatty acids as the main respiratory substrate leads to increased production of ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate) [97]. Currently, there are some evidence showing that ketogenic diet possesses anti-inflammatory effects and leads to short-term improvements in some cardiovascular risk factors and reduction in blood pressure [98100]. However, there are still lacks of promising results to show that ketogenic diet or LCHFD is beneficial to vascular function.

In endothelial cells, ketone bodies significantly induce the expression of genes involved in the cellular antioxidant defense system (Nrf2 and HO-1) and reduce DNA damage against oxidative insult [101]. Ketogenic diet can also reduce glucose metabolism and improve heart function in a mice model with endothelial-specific Notch inhibition. [102]. However, the beneficial effect of ketogenic diet or LCHFD is still questionable, especially in human studies. Indeed, in ApoE knockout mice, LCHFD has no effect on oxidative stress markers, but accelerates atherosclerosis and reduces endothelial progenitor cells [103]. A study of Swedish women suggests that low-carbohydrate diets are associated with an increased risk of cardiovascular diseases [104]. A case-control study shows that ketogenic diet can promote arterial stiffening and endothelial damage in children and young adults with epilepsy [105]. In addition, LCHFD shows no improvement of endothelial function (flow-mediated dilation) in normal weight, young, healthy women [106], while LCHFD may lead to a reduction in flow-mediated dilation and predispose the endothelium to hyperglycemia-induced damage in healthy young adults [107]. Indeed, the detrimental effect of ketogenic diet may be attributed to the formation of advanced glycation end (AGE) products, which promote vascular damages [108]. Although the beneficial effects of ketogenic diet or LCHFD on metabolic parameters are relatively promising, further researches are warranted to investigate the effect of ketogenic diet or LCHFD on cardiovascular health.

4.4. Mediterranean Diet

Mediterranean diet is characterized by high plant proteins, monounsaturated fat, and low animal products and saturated fat. The Mediterranean diet refers to an eating pattern of the olive growing areas surrounding the Mediterranean Sea. Numerous epidemiologic and intervention studies have shown that Mediterranean diet characterized by high consumption of vegetables, fish, olive oil, and moderate wine consumption is associated with a positive effect on endothelial function and a lower incidence of cardiovascular diseases [109111]. Close adherence to a Mediterranean diet improves endothelial function (increased flow-mediated dilation) in obese subjects [109].

Indeed, Mediterranean diet is encompassed of nutrition and cultural behavior such as lifestyle and physical exercise [112]. The exact mechanism of which the Mediterranean diet has cardioprotective effects is thereby uncertain, but it is suggested that antioxidant and anti-inflammatory effect, improvement in endothelial function, and lipid profile are possible mechanisms [111]. Mediterranean diet has been shown to reduce blood pressure in hypertensive women and associate with increased plasma levels of NO and ET-1 and upregulated eNOS and ET-1 receptor in the endothelium [113]. Also, consumption of Mediterranean diet induces a reduction in endothelial damage and dysfunction, which is associated with an improvement in the regenerative capacity of the endothelium in healthy elderly subjects [114]. In randomized clinical trials, Mediterranean diet has been shown to significantly reduce circulating ox-LDL and inflammation markers in high cardiovascular risk subjects [115], as well as reduce oxidative stress and endothelial senescence in elderly subjects [116]. However, contradictory result has also been shown about the effect of the Mediterranean diet on endothelial function. In a clinical trial, treatment for 4 weeks with a Mediterranean-inspired diet fails to show beneficial effect in vascular function and reduce oxidative stress in healthy individuals with a low-risk profile for cardiovascular disease [117].

One special feature of Mediterranean diet is the consumption of olive oil, which is characterized by the high ratio monounsaturated to saturated fat. Consumption of olive oil-rich diet can decrease blood pressure and improve endothelial function in young women, which is associated with reduction in oxidative stress and inflammation mediators, such as ox-LDL and CRP levels [118]. However, our recent study suggests that olive oil, when compared to red fruit (Pandanus conoideus Lam) oil, has no significant effects on eNOS phosphorylation, NO production, and ROS levels in endothelial cells [119]. The favorable effect of Mediterranean diet on endothelial function might also be attributed to other components of this diet such as red wine and fish oil, as well as exercise which will be discussed below. Nevertheless, Mediterranean diet may represent a therapeutic strategy to reduce oxidative stress and inflammation and improve the associated metabolic and cardiovascular risk.

4.5. Calorie Restriction

Calorie restriction is the most potent and reproducible dietary interventions that shows beneficial effect in extending lifespan and attenuating aging-related chronic diseases including obesity and endothelial dysfunction [120].

In animal studies, caloric restriction is achieved by reducing calorie intake by 20-50% of ad libitum intake without altering the proportion of nutrients and inducing malnutrition [120]. Calorie restriction has been shown to improve life span, as well as physiological functions in most experimental models from yeast to nonhuman primates [121123]. Short-term caloric restriction can prevent aging-induced endothelial dysfunction, at least partially by reversing altered iNOS/eNOS ratio, reducing oxidative stress, and increasing SOD enzyme activity in rat [124]. In both young and old mice, caloric restriction can reverse endothelial dysfunction by enhancing eNOS activity and NO production [125127].

In human studies, lifelong caloric restriction has been shown to prolong lifespan, reduce atherosclerosis, and improve endothelial function [124, 128]. The most widely explored mechanisms of the beneficial effects of calorie restriction include improving cardiovascular risk-factor profile, reducing superoxide production and vascular oxidative stress, lowering circulating inflammatory cytokines, and upregulating sirtuin 1 (SIRT1) expression [129]. SIRT1 is a known longevity protein which can stimulate eNOS expression and activity [126, 130]. In response to caloric restriction, SIRT1 is activated and upregulates the activity of eNOS via deacetylating eNOS on lysine 496 and 506 residues [126, 131]. On the other hand, inhibition of SIRT1 prevents endothelium-dependent vasodilation and reduces NO bioavailability, suggesting that NO-mediating effect of caloric restriction is regulated via SIRT1 [132].

Although the translatability of caloric restriction to humans can be debatable, randomized trial has shown that a two-year 25% caloric restriction can attenuate biological aging and reduce the risk of cardiovascular diseases in nonobese young and middle-aged adults [133, 134]. Low-calorie diet can also improve endothelium-dependent vasodilation in obese patients with existing hypertension [135]. Long-term (>6.5 years) of caloric restriction has significantly reduced blood pressure comparing to that prior to the initiation [136]. Alternate day fasting with a low-fat diet for 12 weeks can effectively reduce weight and improve endothelial function (flow-mediated dilation) in both normal weight and overweight adults [137]. Collectively, these data suggest that short to long-term caloric restriction or reduced calorie intake may be able to prevent as well as reverse endothelial dysfunction and cardiovascular complications that caused by aging and obesity.

4.6. Diet Components and Supplements
4.6.1. Alcohol and Wine

A large number of clinical trials and epigenetics studies have strongly correlated the long-term consumption of polyphenol-rich diet with protection against chronic diseases such as cancers and cardiovascular diseases [138140]. Red wine contains numerous amounts of polyphenols which possess antioxidant and anti-inflammatory properties [141]. Resveratrol (3,5,4-trihydroxy-trans-stilbene) is a plant polyphenol found mainly in grape fruits and red wine [142, 143]. Resveratrol is well-studied for its beneficial effect in cardiovascular protection by increasing NO production in the endothelium. Resveratrol can upregulate eNOS expression, stimulate eNOS activity, and prevent the uncoupling of eNOS [144]. In addition, resveratrol can improve endothelial function by activating SIRT1 [145]. Also, resveratrol has been shown to attenuate ox-LDL-induced cytotoxicity, apoptosis, ROS generation, and intracellular calcium accumulation in endothelial cells [39]. Therefore, red wine has been shown to improve endothelial function and reduce oxidative stress and the risk of cardiovascular events in both human and animal studies [146148]. The beneficial effects of long-term consumption of moderate amounts of red wine can be attributed to increased HDL and reduction of ET-1 expression [149], as well as upregulation of sGC [150] and antioxidant enzymes (SOD and HO-1) [148]. Nevertheless, human clinical trials have shown that the beneficial effects of polyphenol are not always achievable within the context of moderate alcohol consumption as the bioavailability of the polyphenolic metabolites that reach the human body are always very low.

Indeed, recent studies suggest the potential influence of ethanol on endothelial functions [151, 152]. Both cross-sectional and randomized clinical trials have suggested that moderate alcohol consumption can improve endothelial function in healthy subjects [151, 153155]. Chronic low ethanol consumption has also been shown to reduce systolic blood pressure and improve endothelial function in rat [156]. Moderate alcohol exposure (up to 1 drink or 12.5 g alcohol per day for women and 2 drinks or 25 g alcohol per day for men [157]) increases the activity of eNOS and NO production from the endothelium in vitro [158160]. These studies suggest that ethanol may increase eNOS gene and protein expressions in endothelial cells. However, there are still controversies in the finding from the human studies. Flow-mediated dilation is impaired in either moderate or excessive alcohol consumption group according to a Japanese study [161]. Although the results from clinical studies of moderate/habitual alcohol consumption remain controversial, one must bear in mind that excessive alcohol consumption is unquestionably harmful to human health at several levels.

4.6.2. Coffee

Coffee is one of the most popular pharmacologically active beverages, which is rich in plant phenolic compounds [162]. Various epidemiologic studies have already shown inverse associations of regular consumption of coffee with metabolic diseases including obesity and type 2 diabetes, as well as with cardiovascular diseases [163166]. The beneficial effect of coffee in improving vascular function appears to be attributed by reducing the ROS production and enhancing NO bioavailability [167]. In a randomized, placebo-controlled, cross-over study, flow-mediated dilation response is significantly improved in the subjects taking caffeinated coffee compared to both groups taking decaffeinated coffee or water, suggesting that the consumption of caffeinated coffee can improve endothelial function [168]. Moreover, the acute administration of caffeine augments endothelium-dependent vasodilation in healthy young men associated with an increased NO production [169]. Indeed, coffee has been described as probably the most relevant source of dietary antioxidants [170]. A few studies have documented that a single serving of coffee may increase plasma antioxidant capacity by around 5% [170172]. Caffeine may enhance endothelial cell migration and reendothelialization in part through an AMPK-dependent mechanism [173]. The most abundant polyphenol in coffee, chlorogenic acid (CGA), has been shown to increase the production of NO and reduce oxidative damages in isolated mice aortic ring [174]. However, the effects of coffee consumption on endothelial function are still controversial. Some studies have suggested an adverse effect of coffee consumption in endothelial function and blood pressure [172, 175]. These controversies may be attributed by the different additional supplements added to the coffee, including sugar and milk. Nevertheless, as coffee is a popular beverage worldwide, the effect of caffeine on endothelial function warrants detailed researches.

4.6.3. Gluten

Gluten consists of two classes of proteins, prolamin, and glutenin and can be found in several kinds of cereal. Gliadin, the wheat prolamin, is not fully digested by intestinal enzymes and is metabolized to biologically active peptides with cytotoxic activities, including increased intestinal permeability and modulation of the immune system [176]. Celiac disease is an autoimmune and systemic disease that develops in genetically susceptible individuals as a result of a permanent intolerance to gluten [177]. Celiac disease is also associated with endothelial dysfunction [178]. Gluten-free diet can reduce the risk for endothelial dysfunction [179] and reduce oxidative stress [180] in patients with celiac disease.

In individuals without celiac disease, the physiological effect of gluten intake is relatively unknown. Wheat alpha-amylase/trypsin inhibitors (ATIs) are activators of the innate immune system via activating toll-like receptor 4 (TLR4) in myeloid cells, triggering several autoimmune/inflammatory diseases. Gluten-containing cereals have been shown to contain the high concentration of ATIs that activate TLR4 [181]. Wheat ATIs are implicated in the pathogenesis of celiac disease as well as nonceliac wheat sensitivity [182]. Mice on a gluten-free diet show significantly attenuated clinical parameters of kidney dysfunction (proteinuria, haematuria, and hemoglobinuria) and serum inflammatory cytokines (IL-6 and TNF-α) compared to mice on a gluten-containing diet [183]. Increased gluten intake is associated with increased concentrations of plasma inflammatory marker, α2-macroglobulin, in young adults without celiac disease [184]. Also, gluten diet can exacerbate vascular oxidative stress and inflammation and accelerate atherosclerosis in ApoE knockout mice [185]. Gluten feeding has been shown to elevate the rate of superoxide and nitrotyrosine production in the aortic root lesion [185]. These results suggest that the potential use of gluten-free diet is an alternative to ameliorate cardiovascular diseases independent of celiac disease.

4.6.4. Dark Chocolate

The main compound in chocolate is cocoa, which contains high content of polyphenols, while dark chocolate contains a greater amount of cocoa compared with milk chocolate [186]. Chocolate and cocoa have been described as one of the most important sources of flavonoids in the human diet [187, 188]. Data currently available suggests that daily consumption of cocoa-rich chocolate may partially reduce the risk of cardiovascular disease [189].

Several mechanisms of how chocolates or cocoa flavonoids are protective against cardiovascular disease have been proposed including improving endothelial function, decreasing blood pressure, possessing antioxidant, antiplatelet, and anti-inflammatory effects, as well as a positive modulation of insulin resistance [187, 190192].

Cocoa has been shown to reduce oxidative stress via lowering the activation of NADPH oxidase and stimulating NO-mediated vasorelaxation [193, 194]. In a cross-sectional study, administration of dark chocolate (>85% cocoa), but not milk chocolate (<35% cocoa), can significantly improve flow-mediated dilation and NO bioavailability in patients with nonalcoholic steatohepatitis [195]. In another study, dark chocolate, but not milk chocolate, inhibits platelet activity and oxidative stress in smokers [194]. And both studies suggest that dark chocolate reduces oxidative stress by downregulating NOX2.

Administration of a single dose of cocoa is dose dependently associated with significant increases in circulating flavanols and flow-mediated dilation in medicated type 2 diabetes patients [190]. In a randomized trial, the acute ingestion of either solid dark chocolate or liquid cocoa improves endothelial function and reduces blood pressure in overweight adults, while sugared cocoa may have attenuated these beneficial effects [196]. These studies suggest that the consumption of sugar-free dark chocolate would be the ideal choice to prevent endothelial dysfunction and cardiovascular diseases.

4.6.5. Omega 3 Polyunsaturated Fatty Acids

The correlation between high omega 3 polyunsaturated fatty acids (n-3 PUFAs) and low incidence of cardiovascular disease has been long recognized since an epidemiological study in the 1970s [197]. The broad range of beneficial effects of n-3 PUFAs is well known, including antiatherogenic, antithrombogenic, and blood pressure lowering [198]. Replacement of saturated fat with unsaturated fat has been suggested to improve endothelial function and show beneficial effect on endothelial repair and maintenance [199]. One of the mechanisms by which n-3 PUFAs influence endothelial function is mediated by their incorporation into biological membrane phospholipids and modulation of membrane composition and fluidity [200]. Caveolae-associated receptors mediate important pathways such as the NO-cGMP pathway, and the NADPH oxidase and TNF-α-NF-κB mediated COX-2 and PGE2 activation pathway [201, 202]. n-3 PUFAs may exert their beneficial effects in the endothelium, by modulating the composition of membrane caveolae, similar as other lipids [203].

n-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to protect the cardiovascular system, in part, by enhancing eNOS activity and NO production [204, 205]. In various animal models, n-3 PUFAs have been shown to increase NO production by directly stimulating eNOS gene and protein expression, which improve vasodilation [206208]. In addition to enhancing NO production, n-3 PUFAs also decrease oxidative stress. In endothelial cells, n-3 PUFAs can reduce the levels of inflammatory cytokines (IL-6 and TNF-α) and oxidative stress markers (ROS and malondialdehyde (MDA)) and increase the activity of SOD [209]. EPA and DHA have been shown to attenuate oxidative stress-induced DNA damage in endothelial cells through the upregulation of NRF2-mediated antioxidant response [210]. In epidemiology studies and clinical trials, n-3 PUFA supplementation prevents the development of atherosclerotic diseases [211, 212]. Moreover, n-3 PUFA supplementation has been shown to improve endothelial function in patients with primary antiphospholipid syndrome [213], type 2 diabetes [214], peripheral arterial disease [215], heart failure [216], and hypertriglyceridemia [217].

Recently, a ratio of EPA : DHA 6 : 1 has been recognized as a potent formulation to improve endothelial functions in different studies. Intake of omega-3 formulation EPA : DHA 6 : 1 can restore endothelium-dependent NO-mediated relaxations, most likely, by preventing the upregulation of the local angiotensin system, NADPH oxidase, and the subsequent formation of ROS in old rats [218]. Also, EPA : DHA 6 : 1 can prevent endothelial senescence in middle-aged or old rats by limiting both the shedding of endothelial microvesicles and their prosenescent, prothrombotic, and proinflammatory effects in endothelium [218]. However, a recent clinical study suggests that high-dose n-3 PUFA treatment in very high-risk patients with atherosclerotic cardiovascular disease and type 2 diabetes cannot improve the endothelial function indices [219]. Therefore, stronger evidence is needed before large-scale prescription of n-3 PUFAs in very high-risk patients. In overall, n-3 PUFAs have high potential to beneficially impact endothelial function and cardiovascular outcome.

4.6.6. Vitamins

Antioxidant vitamins (vitamins C, vitamin E, and β-carotene) appear to have beneficial effects on vascular endothelial function [220, 221]. β-carotene belongs to the family of carotenoids which are lipid-soluble plant pigments. β-carotene has been demonstrated to reduce inflammatory response and oxidative stress in TNF-α-treated endothelial cells in vitro [222], to prevent LDL oxidation [223], and to reduce the risk of atherosclerosis [224] and the incidence of cardiovascular diseases [223, 225, 226]. It has been shown that vitamin C (a water soluble antioxidant) and vitamin E (a lipid-soluble antioxidant) improve endothelial function by normalizing the expression of eNOS in hypercholesterolemic pigs [227]. Simultaneous administration of vitamins C and E can prevent the deleterious effects of postprandial hypertriglyceridemia on endothelial-dependent vasodilation [77].

In a randomized, placebo-controlled study, supplementation containing vitamin C (1000 mg/d) and vitamin E (400 IU/d) shows beneficial effects on glucose and lipid metabolism, blood pressure, and arterial elasticity in patients with cardiovascular risk factors [228]. Possible mechanisms for the beneficial effects of vitamins C and E on endothelial function could be attributed by eliminating superoxide and scavenging lipid hydroperoxyl radicals, and thereby maintaining NO bioavailability [220]. Long-term consumption of vitamin C in diabetic patients can improve certain echocardiographic parameters and enhance vascular endothelial function (flow-mediated dilation) [229]. Chronic consumption of vitamin E partially prevents hyperglycemia-induced endothelial dysfunction in diabetic rat, while vitamin E deficiency enhances diabetic endothelial dysfunction dramatically in vivo [230].

Combined treatment with vitamins C and E has beneficial effects on endothelium-dependent vasodilation and arterial stiffness, which are associated with changes in plasma markers of oxidative stress in essential hypertensive patients [231]. However, one should be cautious about the long term or high-dose usage of vitamin. Vitamin C has been shown to increase the production of AGE products in diabetic patients [232]. Long-term treatment with 1,800 IU of vitamin E has no beneficial effects on endothelial or left ventricular function in diabetic patients, and some vitamin E-treated patients has a worsening in some vascular reactivity measurements when compared with control subjects [231].

5. Physical Exercise

Sedentary lifestyle and overconsumption of energy-rich food have been identified as a risk factor for the development of some cardiovascular complications [233, 234]. In comparison, regular physical activity (child and adolescents: 60 mins of moderate-to-vigorous physical activity daily; adults: 150 to 300 mins of moderate intensity per week [235]) has long been considered necessary for the achievement and maintenance of optimal health. Prospective studies provide direct evidence that a physically active lifestyle delays all-cause mortality, extends longevity [236], and reduces risk for cardiovascular mortality by 42–44%, compared to sedentary lifestyle [237]. The terms “physical activity” and “physical exercise” refer to body movements by the skeletal musculature and associated with the consumption of energy. Specifically, the term “physical training” indicates a regular, structured physical activity to improve and/or maintain physical fitness and well-being [238]. Exercise training elicits beneficial effects in a number of physiological adaptations, including maximal oxygen consumption (VO2max), cardiac output, and maximal oxygen extraction, as well as maximal skeletal muscle blood flow capacity [239]. It is commonly recognized that physical training has beneficial effects on body composition and health, especially for weight loss [240], and also known as a nonpharmacological treatment of cardiovascular diseases [241].

5.1. Physical Exercise and Laminar Shear Stress

Regular exercises result in numerous health benefits, such as improving body composition and endothelial function and preventing insulin resistance, oxidative stress, and arterial hypertension [241]. One of the important mechanisms to improve endothelial function during exercising is the increased blood flow and shear stress which can improve vascular homeostasis by reducing the production of ROS and increasing the bioavailability of NO in the endothelium (discussed above) [242]. During exercising, repeated episodes of increased blood flow elicit an improvement in endothelial function and lead to the long-term benefits of regular exercise that prevent risk of cardiovascular diseases [243]. This mechanism is likely to involve chronic upregulation of NO production mediated by an enhanced expression of eNOS.

It is suggested that shear stress-mediated effects and consequent production and bioactivity of NO differ qualitatively and quantitatively according to the exercise involved [244]. Vascular laminar shear stress increases during exercise and is associated with a rapid upregulation of eNOS gene and protein expressions [245]. Varied durations of exercise training seem to influence the response of arteries to increase flow and shear stress [244]. It has been reported that improvement in NO-related vasodilation is observed in short- to medium-term training, whereas longer-term training is associated with arterial remodeling [244]. It is also important to note that laminar shear stress due to exercise has a predominant antioxidant effect and improves endothelial function, while oscillatory shear stress in hypertension is associated with opposite effects promoting oxidative stress and oxidative vasculature damage through a progressive increase in NADPH activity [246].

5.2. Physical Exercise, Arterial Pressure, and Oxidative Stress

Indeed, exercise is a double-edged sword for endothelial function [247]. Blood pressure distends arteries and causes stretching in vascular cells. Changes in pressure consequently generate circumferential stress (strain) in the compliant arteries. During exercise, because of increased heart rate and systolic pressure, expansion of arteries can induce cyclic circumferential strain on endothelial cells [248, 249]. Cyclic circumferential strain can also be increased by the relaxation of vascular smooth muscle, which induces vasodilation and stretching of the endothelium. The effects of cyclic circumferential strain are complex and variable. Increased exposure to cyclic circumferential strain has been shown to alter gene expressions in the endothelium [including eNOS and EDHF synthase (CYP450)] and promote the production of ROS, the expression of ICAM, selectin, and monocyte chemoattractant protein-1 (MCP-1) [250]. Indeed, chronic high blood pressure is associated with endothelial dysfunction and progression of atherosclerosis [251]. The major effect of increased cyclic circumferential strain on endothelial cells appears to be ROS-mediated proatherogenic [252]. The pattern of change in cyclic circumferential strain is relevant as transient increases in blood pressure and ROS production, which is associated with exercise bouts and may increase eNOS expression and other beneficial effects of exercise, whereas chronic increases in blood pressure may chronically elevate ROS, causing maladaptation [249]. Although it has been suggested that short-term exercise can cause oxidative stress by increasing LDL susceptibility to oxidation or vascular superoxide production [253], long-term and/or regular exercise has been shown to reduce oxidative stress and upregulate the expression of SOD [254] and other antioxidant defenses in human, which leads to positive arterial remodeling to normalize blood pressure and shear stress [255258].

5.3. Physical Exercise and Arterial Remodeling

Arterial remodeling is the active process of structural alteration that occurs as a result of cell death, proliferation, and migration as well as changes in the extracellular matrix of a vessel and is controlled by the crosstalk between endothelium and vascular smooth muscle cells [259]. Sensitivity to shear stress of endothelium is important in arterial remodeling and can activate signaling pathways in vascular smooth muscle cells [259]. Vasculature in hypertensive individuals undergoes accelerated vascular wall thickening and leads to degeneration and calcification of the vascular wall and vessel stiffening, while compensatory vessel wall enlargement is observed in atherosclerotic patients [260].

NO is an important endothelial regulator of flow- and pressure-induced arterial remodeling [260], while the congenital absence of eNOS causes adverse vascular remodeling [24, 261]. Upon long-term exercise training, NO-mediated structural adaptation occurs in the arteries, resulting in a chronic increase in vessel caliber, which structurally normalizes shear stress and cyclic circumferential strain (Figure 2). NO function is then returned towards baseline levels [262]. This process constitutes a long term and structural change mechanism for reducing shear stress, allowing NO bioactivity to return towards pretraining levels [244]. Moreover, positive arterial remodeling serves to enhance muscle performance by increasing the oxygen-exchange capacity and by increasing blood flow capacity. These adaptations potentially contribute to cardiovascular performance and health benefits in individuals who have long-term exercise training [262].

5.4. Physical Exercise in Animal Models

In healthy rats, a single resisted exercise session can improve endothelial function and NO synthesis in both the endothelium and the smooth muscle layer of mesenteric and promote insulin-induced vasodilation [263]. It is proposed that exercise stimulates factors that increase endothelial NO production including vascular distension, catecholamine release, and intermittent hypoxia. Exercise training in pigs [264] and hypertensive rats [265] has been shown to increase both gene and protein expression of eNOS. It is also suggested that the stimulation of NO production is dependent on the volume of exercise, and a greater demand of oxygen and nutrients is involved in the beneficial effects of exercise on the endothelium [263, 266]. Moreover, similar results are observed in hypertensive rats that single session of resisted exercise activates eNOS and promotes vasorelaxation [267]. Interestingly, expression of the prooxidant enzyme, NADPH oxidase, is reduced by exercise training in hypertensive rats, which may have a beneficial effect on the half-life of NO in the vascular wall [266]. These data reinforce that exercise can improve endothelial function, probably by stimulating NO production, even in hypertension. In diabetic rats, exercise training has been shown to normalize the diabetes-related endothelial dysfunction and improve insulin sensitivity [268, 269]. Moderate-intensity exercise reverses diabetes-related endothelial dysfunction independently of improvements in body weight or hyperglycemia in db/db mice. It is suggested that upregulations of eNOS and cytosolic Cu/Zn-SOD, but not MnSOD, play important roles in improving NO bioavailability, as well as in reversing endothelial dysfunction in diabetes via exercise [270]. In aging rats, exercising training increases sensitivity of blood vessel to shear stress and promotes acetylcholine-induced endothelial-dependent vasorelaxation [271], suggesting that exercising training is able to reverse age-related decline in vascular function.

In addition, long period of exercise can reduce the contractile response of the aorta to noradrenaline and increase the relaxation induced by acetylcholine in healthy rats [272274], suggesting that the time of exercise exposure may also be critical to determine the beneficial effects of exercise on endothelial function. Chronic exercise training improves aortic endothelial and mitochondrial function through an adenosine monophosphate-activated protein kinase α2 (AMPKα2)-dependent manner in mice, which is also associated with increased mitochondrial antioxidative capacity (increased expression of MnSOD and catalase) [275]. These experimental studies suggest that physical exercise plays an important role in the prevention and treatment of endothelial dysfunction. However, additional studies are needed to establish the best kind, intensity, and duration of exercise to allow more efficient prescribing in clinical area.

5.5. Physical Exercise in Human Studies

In type 2 diabetic patients, lower-intensity exercise has physiological meaningful effects on endothelial function, while low to moderate intensity and aerobic exercises significantly increase flow-mediated vasodilation more than moderate- to high-intensity exercises and combined aerobic and resistance exercises, respectively [276]. Regular physical activity has been shown to promote the activities of antioxidant enzymes and stimulate glutathione levels in body fluids [277, 278]. In young prehypertensive patients, resistance training increases flow-mediated dilation and reduces blood pressure [279], as wells as improves resistance artery endothelial function and prooxidant/antioxidant balance [280]. In a recent randomized clinical trial, aerobic exercise training, resistance training, and combined training have also shown similar beneficial in improving endothelial function but impacts on ambulatory blood pressure appear to be variable in middle-aged and older individuals with prehypertension or hypertension [281].

Aerobic exercise increases both gene and protein expression of eNOS in patients with coronary artery disease [245]. Six-month exercise training reduces arterial blood pressure and is associated with increased NO content (determined by plasma nitrite/nitrate levels) in hypertensive women [282]. However, biological sample acquisition from humans subjected to physical exercise is challenging, thereby the changes in NO production are predominantly evaluated based on the measurements of NO content in the exhaled air. Physical training is associated with an increase in NO content in the exhaled air [283], while some studies suggest a reduced NO content in the exhaled air after physical exercise [284286]. This controversy is unsurprising due to the complexity of NO exchange and multisystemic nature of the physiological responses to physical exercise [249].Nevertheless, variations of NO content in the exhaled air may also depend on the levels of physical activity [284].

5.6. High-Intensity Exercise: Good or Bad?

It is clinically important to select the appropriate intensity, duration, frequency, and kind of exercise, as high-intensity exercise can be harmful to human vessels [287]. In general, the guidelines for patients with mild-to-moderate essential hypertension recommend exercise at an intensity of around 50% of maximum oxygen consumption, such as walking, jogging, cycling, or swimming, for 30 minutes and 5 to 7 times per week [287289]. In recent years, low-volume high-intensity exercise training has become advocated with data showing comparable benefits to traditional endurance-based training in skeletal muscle metabolic control and cardiovascular system function [290]. Aerobic training of high intensity, compared to the aerobic training of low intensity and controls, has been shown to improve endothelium function (flow-mediated vasodilatation) in patients with metabolic syndrome or diabetes [291]. Both continuous moderate-intensity aerobic exercise and high-intensity interval aerobic exercise can significantly improve endothelial function, in terms of flow-mediated dilation, the carotid femoral pulse wave velocity and the femoral dorsalis pedis pulse wave velocity in health men [292]. A recent randomized controlled, crossover study also suggests that short-duration maximal intensity exercise has comparable effects on endothelial function and oxidative stress with mild and moderate exercise [293].

On the other hand, collective evidence has suggested that production of ROS is greater than production of NO during high-intensity exercise, resulting in reduced endothelial function (Figure 3). For example, high-intensity exercise training has no beneficial effects on endothelial function in spontaneous hypertensive rat, but rather augments oxidative stress, resulting in eNOS uncoupling and ROS production and leading to further decrease in NO bioavailability and increase in ROS [294]. High-intensity exercise also increases the indices of oxidative stress, including plasma concentration of 8-hydroxy-2-deoxyguanosine (8-OHdG) and serum concentration of ox-LDL, and decreases endothelium-dependent vasodilation in healthy men [295]. It is suggested that the massive increase in oxygen uptake that occurs in skeletal muscle during high-intensity exercise is associated with an increase in ROS [296]. Moreover, oxidation of tetrahydrobiopterin (BH4) is suggested to be responsible in oxidative stress-induced eNOS uncoupling during high-intensity exercise. BH4 deficiency is associated with the ROS production from dysfunctional eNOS; superoxide produced by uncoupled eNOS which also inactivates NO [297]. It has also been reported that the degradation of BH4 by ROS is associated with the inhibition of eNOS [297, 298]. These findings suggest that BH4 deficiency-induced eNOS dysfunction causes endothelial dysfunction in hypertension through promoting oxidative stress. It is possible that high-intensity exercise activates oxidative stress through exacerbation of BH4 deficiency, as well as oxidation of BH4. These data may suggest that high-intensity exercise increases oxidative stress in humans, which diminishes endothelium-dependent vasodilation.

Recently, high-intensity interval training (HIIT) has been proposed to have positive effects on metabolic profile and improves cardiovascular health [299301] and used as an alternative to traditional endurance training to promote metabolic and cardiovascular health. The detailed mechanisms responsible for the beneficial effect of HIIT are not well known, but one proposed mechanism is that HIIT increases aerobic capacity and thus delays the onset of exhaustion [302]. The common formula of HIIT involves a 2 : 1 work-to-recovery ratio [303]. Interval running (30 s at VO2max alternated with 30 s at 50% VO2max) has been shown to provide a greater exercise training stimulus than continuous running to improve VO2max [304]. In general, HIIT elicits greater aerobic capacity adaptations compared to chronic training in improving cardiovascular risk [303]. Recently, HIIT has been shown to improve arterial stiffness, cardiovascular health, and metabolic profiles in inactive individuals with obesity and type 2 diabetes [305307]. Future studies are warranted to investigate the effects and underlying mechanisms of HITT on endothelial function in a different pathophysiological condition, including aging, diabetes, and hypertension.

5.7. Exercise and Diet Combination

In order to maximize the beneficial effects of exercise on vascular function, the combination with a healthy diet is reasonable. Most current studies support that exercise is effective to ameliorate HFD-induced endothelial dysfunction and improve microvascular reactivity in young, healthy men [308], as well as to improve insulin action and reductions in glycemia and prevent endothelial dysfunction after high-sugar-food ingestion with endurance exercise performed on the previous day [80]. In addition, it is also suggested that the combination of supervised diet and exercise training is effective to improve vascular function and multiple adolescent obesity-related end points [309]. In addition, interval exercise combined with a low-calorie diet improves endothelial function in obese adult female [310]. Moreover, a recent study has demonstrated that aerobic exercise prior to a high-sugar meal has no improvement on endothelial function, blood glucose, insulin, ET-1 or NO concentrations, or insulin sensitivity in postmenopausal women [311]. Therefore, it is synergistic to improve vascular function when proper exercise is carried out in parallel with a healthy diet.

6. Conclusions

Healthy lifestyle and diet are important in reducing the risk for metabolic and cardiovascular diseases. A large body of evidence underlines the importance of proper diet and physical exercise in preventing oxidative stress and endothelial dysfunction, which are risk factors for cardiovascular diseases. Diet is an important source for antioxidants. In general, consumption of balanced diet with reduced amount of added sugar and saturated fat has been shown to reduce oxidative stress and promote endothelial function. However, it has been suggested that the indiscriminate use of antioxidants may even be harmful, since basal levels of ROS are imperative for certain cellular functions [312]. Overconsumption of certain nutrients as well as overintensive exercise may impede some essential cellular defense mechanisms. A fine balance between oxidative stress and antioxidants is important for normal function in the cells, and interfering with this balance may lead to unfavorable effects. While the best diet composition and exercise intensity may vary among individuals and physiological conditions, further detailed studies are needed. Thereby, before the ultimate problem is solved, a balanced diet and regular exercise are always helpful.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Authors’ Contributions

AWCM wrote the initial draft of the manuscript. HL and NX critically reviewed and edited the manuscript. All authors agreed to its publication.

Acknowledgments

Original works from the authors’ laboratory contributing to this review were supported by grants LI-1042/1-1, LI-1042/3-1, LI-1042/5-1, and XI 139/2-1 from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany. HL and NX were supported by research grants from the Boehringer Ingelheim Foundation for the collaborative research consortium “Novel and neglected cardiovascular risk factors: molecular mechanisms and therapeutic implications”.

References

  1. A. Persynaki, S. Karras, and C. Pichard, “Unraveling the metabolic health benefits of fasting related to religious beliefs: a narrative review,” Nutrition, vol. 35, pp. 14–20, 2017. View at: Publisher Site | Google Scholar
  2. C. R. D'Adamo and A. Sahin, “Soy foods and supplementation: a review of commonly perceived health benefits and risks,” Alternative Therapies in Health and Medicine, vol. 20, Supplement 1, pp. 39–51, 2014. View at: Google Scholar
  3. S. Andres, S. Pevny, R. Ziegenhagen et al., “Safety aspects of the use of quercetin as a dietary supplement,” Molecular Nutrition & Food Research, vol. 62, no. 1, 2018. View at: Publisher Site | Google Scholar
  4. V. Rani, G. Deep, R. K. Singh, K. Palle, and U. C. S. Yadav, “Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies,” Life Sciences, vol. 148, pp. 183–193, 2016. View at: Publisher Site | Google Scholar
  5. H. Sies, “Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: oxidative eustress,” Redox Biology, vol. 11, pp. 613–619, 2017. View at: Publisher Site | Google Scholar
  6. C. M. Sena, A. Leandro, L. Azul, R. Seiça, and G. Perry, “Vascular oxidative stress: impact and therapeutic approaches,” Frontiers in Physiology, vol. 9, p. 1668, 2018. View at: Publisher Site | Google Scholar
  7. S. Joshi, R. J. Ostfeld, and M. McMacken, “The ketogenic diet for obesity and diabetes-enthusiasm outpaces evidence,” JAMA Internal Medicine, vol. 179, no. 9, article 1163, 2019. View at: Publisher Site | Google Scholar
  8. A. J. Nordmann, K. Suter-Zimmermann, H. C. Bucher et al., “Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors,” The American Journal of Medicine, vol. 124, no. 9, pp. 841–851.e2, 2011. View at: Publisher Site | Google Scholar
  9. S. Golbidi, A. Daiber, B. Korac, H. Li, M. F. Essop, and I. Laher, “Health benefits of fasting and caloric restriction,” Current Diabetes Reports, vol. 17, no. 12, p. 123, 2017. View at: Publisher Site | Google Scholar
  10. A. Stanek, B. Fazeli, S. Bartuś, and E. Sutkowska, “The role of endothelium in physiological and pathological states: new data,” BioMed Research International, vol. 2018, Article ID 1098039, 3 pages, 2018. View at: Publisher Site | Google Scholar
  11. G. H. Gibbons and V. J. Dzau, “The emerging concept of vascular remodeling,” The New England Journal of Medicine, vol. 330, no. 20, pp. 1431–1438, 1994. View at: Publisher Site | Google Scholar
  12. A. Sandoo, J. J. C. S. Veldhuijzen van Zanten, G. S. Metsios, D. Carroll, and G. D. Kitas, “The endothelium and its role in regulating vascular tone,” Open Cardiovascular Medicine Journal, vol. 4, no. 1, pp. 302–312, 2010. View at: Publisher Site | Google Scholar
  13. N. Xia, U. Förstermann, and H. Li, “Effects of resveratrol on eNOS in the endothelium and the perivascular adipose tissue,” Annals of the New York Academy of Sciences, vol. 1403, no. 1, pp. 132–141, 2017. View at: Publisher Site | Google Scholar
  14. H. Ogita and J. Liao, “Endothelial function and oxidative stress,” Endothelium, vol. 11, no. 2, pp. 123–132, 2009. View at: Google Scholar
  15. A. M. Cuevas and A. M. Germain, “Diet and endothelial function,” Biological Research, vol. 37, no. 2, pp. 225–230, 2004. View at: Google Scholar
  16. P. Rajendran, T. Rengarajan, J. Thangavel et al., “The vascular endothelium and human diseases,” International Journal of Biological Sciences, vol. 9, no. 10, pp. 1057–1069, 2013. View at: Publisher Site | Google Scholar
  17. V. M. Miller and P. M. Vanhoutte, “Enhanced release of endothelium-derived factor (s) by chronic increases in blood flow,” The American Journal of Physiology, vol. 255, 3, Part 2, pp. H446–H451, 1988. View at: Google Scholar
  18. J. Tao, Z. Yang, J. M. Wang et al., “Shear stress increases Cu/Zn SOD activity and mRNA expression in human endothelial progenitor cells,” Journal of Human Hypertension, vol. 21, no. 5, pp. 353–358, 2007. View at: Publisher Site | Google Scholar
  19. P. M. Vanhoutte, H. Shimokawa, E. H. C. Tang, and M. Feletou, “Endothelial dysfunction and vascular disease,” Acta Physiologica (Oxford, England), vol. 196, no. 2, pp. 193–222, 2009. View at: Publisher Site | Google Scholar
  20. A. Daiber, S. Steven, A. Weber et al., “Targeting vascular (endothelial) dysfunction,” British Journal of Pharmacology, vol. 174, no. 12, pp. 1591–1619, 2017. View at: Publisher Site | Google Scholar
  21. J. Lei, Y. Vodovotz, E. Tzeng, and T. R. Billiar, “Nitric oxide, a protective molecule in the cardiovascular system,” Nitric Oxide, vol. 35, pp. 175–185, 2013. View at: Publisher Site | Google Scholar
  22. H. Bulckaen, G. Prévost, E. Boulanger et al., “Low-dose aspirin prevents age-related endothelial dysfunction in a mouse model of physiological aging,” Heart and Circulatory Physiology, vol. 294, no. 4, pp. H1562–H1570, 2008. View at: Publisher Site | Google Scholar
  23. S. Klöß, A. Bouloumié, and A. Mülsch, “Aging and chronic hypertension decrease expression of rat aortic soluble guanylyl cyclase,” Hypertension, vol. 35, no. 1, pp. 43–47, 2000. View at: Publisher Site | Google Scholar
  24. A. Csiszar, Z. Ungvari, J. G. Edwards et al., “Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function,” Circulation Research, vol. 90, no. 11, pp. 1159–1166, 2002. View at: Publisher Site | Google Scholar
  25. D. Versari, E. Daghini, A. Virdis, L. Ghiadoni, and S. Taddei, “Endothelial dysfunction as a target for prevention of cardiovascular disease,” Diabetes Care, vol. 32, Supplement 2, pp. S314–S321, 2009. View at: Publisher Site | Google Scholar
  26. S. Xu and R. M. Touyz, “Reactive oxygen species and vascular remodelling in hypertension: still alive,” The Canadian Journal of Cardiology, vol. 22, no. 11, pp. 947–951, 2006. View at: Publisher Site | Google Scholar
  27. T. Senoner and W. Dichtl, “Oxidative stress in cardiovascular diseases: still a therapeutic target?” Nutrients, vol. 11, no. 9, p. 2090, 2019. View at: Publisher Site | Google Scholar
  28. E. R. Stadtman, “Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences,” Free Radical Biology & Medicine, vol. 9, no. 4, pp. 315–325, 1990. View at: Publisher Site | Google Scholar
  29. Y. Higashi, K. Noma, M. Yoshizumi, and Y. Kihara, “Endothelial function and oxidative stress in cardiovascular diseases,” Circulation Journal, vol. 73, no. 3, pp. 411–418, 2009. View at: Publisher Site | Google Scholar
  30. D. Tousoulis, I. Andreou, C. Antoniades, C. Tentolouris, and C. Stefanadis, “Role of inflammation and oxidative stress in endothelial progenitor cell function and mobilization: therapeutic implications for cardiovascular diseases,” Atherosclerosis, vol. 201, no. 2, pp. 236–247, 2008. View at: Publisher Site | Google Scholar
  31. M. Soccio, E. Toniato, V. Evangelista, M. Carluccio, and R. de Caterina, “Oxidative stress and cardiovascular risk: the role of vascular NAD (P) H oxidase and its genetic variants,” European Journal of Clinical Investigation, vol. 35, no. 5, pp. 305–314, 2005. View at: Publisher Site | Google Scholar
  32. R. De Caterina, “Endothelial dysfunctions: common denominators in vascular disease,” Current Opinion in Lipidology, vol. 11, no. 1, pp. 9–23, 2000. View at: Publisher Site | Google Scholar
  33. H. Li, S. Horke, and U. Forstermann, “Oxidative stress in vascular disease and its pharmacological prevention,” Trends in Pharmacological Sciences, vol. 34, no. 6, pp. 313–319, 2013. View at: Publisher Site | Google Scholar
  34. T. Münzel, G. G. Camici, C. Maack, N. R. Bonetti, V. Fuster, and J. C. Kovacic, “Impact of oxidative stress on the heart and vasculature,” Journal of the American College of Cardiology, vol. 70, no. 2, pp. 212–229, 2017. View at: Publisher Site | Google Scholar
  35. I. Corre, F. Paris, and J. Huot, “The p 38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells,” Oncotarget, vol. 8, no. 33, pp. 55684–55714, 2017. View at: Publisher Site | Google Scholar
  36. R. Lee, M. Margaritis, K. Channon, and C. Antoniades, “Evaluating oxidative stress in human cardiovascular disease: methodological aspects and considerations,” Current Medicinal Chemistry, vol. 19, no. 16, pp. 2504–2520, 2012. View at: Publisher Site | Google Scholar
  37. U. Forstermann, N. Xia, and H. Li, “Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis,” Circulation Research, vol. 120, no. 4, pp. 713–735, 2017. View at: Publisher Site | Google Scholar
  38. I. Levitan, S. Volkov, and P. V. Subbaiah, “Oxidized LDL: diversity, patterns of recognition, and pathophysiology,” Antioxidants & Redox Signaling, vol. 13, no. 1, pp. 39–75, 2010. View at: Publisher Site | Google Scholar
  39. H. C. Ou, F. P. Chou, H. M. Sheen, T. M. Lin, C. H. Yang, and W. Huey-Herng Sheu, “Resveratrol, a polyphenolic compound in red wine, protects against oxidized LDL-induced cytotoxicity in endothelial cells,” Clinica Chimica Acta, vol. 364, no. 1-2, pp. 196–204, 2006. View at: Publisher Site | Google Scholar
  40. M. Whatnall, C. Collins, R. Callister, and M. Hutchesson, “Associations between unhealthy diet and lifestyle behaviours and increased cardiovascular disease risk in young overweight and obese women,” Healthcare, vol. 4, no. 3, p. 57, 2016. View at: Publisher Site | Google Scholar
  41. H. Kahleova, J. Salas-Salvadó, D. Rahelić, C. W. C. Kendall, E. Rembert, and J. L. Sievenpiper, “Dietary patterns and cardiometabolic outcomes in diabetes: a summary of systematic reviews and meta-analyses,” Nutrients, vol. 11, no. 9, p. 2209, 2019. View at: Publisher Site | Google Scholar
  42. C. Lassale, G. D. Batty, A. Baghdadli et al., “Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies,” Molecular Psychiatry, vol. 24, no. 7, pp. 965–986, 2019. View at: Publisher Site | Google Scholar
  43. L. Mokotedi, F. S. Michel, A. J. Woodiwiss, G. R. Norton, and A. M. E. Millen, “Effects of high salt-low potassium diet on blood pressure and vascular reactivity in male Sprague Dawley rats,” Journal of Cardiovascular Pharmacology, vol. 71, no. 6, pp. 340–346, 2018. View at: Publisher Site | Google Scholar
  44. Y. Du, C. G. Taylor, and P. Zahradka, “Modulation of endothelial cell responses and vascular function by dietary fatty acids,” Nutrition Reviews, vol. 77, no. 9, pp. 614–629, 2019. View at: Publisher Site | Google Scholar
  45. M. Adamo, A. M. Labate, A. Ferrulli, C. Macrì, I. Terruzzi, and L. Luzi, “Effects of hazelnuts and cocoa on vascular reactivity in healthy subjects: a randomised study,” International Journal of Food Sciences and Nutrition, vol. 69, no. 2, pp. 223–234, 2018. View at: Publisher Site | Google Scholar
  46. E. B. Rimm, A. Ascherio, E. Giovannucci, D. Spiegelman, M. J. Stampfer, and W. C. Willett, “Vegetable, fruit, and cereal fiber intake and risk of coronary heart disease among men,” JAMA, vol. 275, no. 6, pp. 447–451, 1996. View at: Publisher Site | Google Scholar
  47. J. C. Stoclet, T. Chataigneau, M. Ndiaye et al., “Vascular protection by dietary polyphenols,” European Journal of Pharmacology, vol. 500, no. 1-3, pp. 299–313, 2004. View at: Publisher Site | Google Scholar
  48. B. C. van Bussel, R. M. A. Henry, I. Ferreira et al., “A healthy diet is associated with less endothelial dysfunction and less low-grade inflammation over a 7-year period in adults at risk of cardiovascular disease,” The Journal of Nutrition, vol. 145, no. 3, pp. 532–540, 2015. View at: Publisher Site | Google Scholar
  49. A. A. Brown and F. B. Hu, “Dietary modulation of endothelial function: implications for cardiovascular disease,” The American Journal of Clinical Nutrition, vol. 73, no. 4, pp. 673–686, 2001. View at: Publisher Site | Google Scholar
  50. R. H. Eckel, J. M. Jakicic, J. D. Ard et al., “2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” Journal of the American College of Cardiology, vol. 63, no. 25, Part B, pp. 2960–2984, 2014. View at: Google Scholar
  51. A. B. Waqar, T. Koike, Y. Yu et al., “High-fat diet without excess calories induces metabolic disorders and enhances atherosclerosis in rabbits,” Atherosclerosis, vol. 213, no. 1, pp. 148–155, 2010. View at: Publisher Site | Google Scholar
  52. R. A. Anderson, M. L. Evans, G. R. Ellis et al., “The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes,” Atherosclerosis, vol. 154, no. 2, pp. 475–483, 2001. View at: Publisher Site | Google Scholar
  53. C. A. Dow, B. L. Stauffer, J. J. Greiner, and C. A. DeSouza, “Influence of habitual high dietary fat intake on endothelium-dependent vasodilation,” Applied Physiology, Nutrition, and Metabolism, vol. 40, no. 7, pp. 711–715, 2015. View at: Publisher Site | Google Scholar
  54. M. Kratz, T. Baars, and S. Guyenet, “The relationship between high-fat dairy consumption and obesity, cardiovascular, and metabolic disease,” European Journal of Nutrition, vol. 52, no. 1, pp. 1–24, 2013. View at: Publisher Site | Google Scholar
  55. M. Graupera and M. Claret, “Endothelial cells: new players in obesity and related metabolic disorders,” Trends in Endocrinology and Metabolism, vol. 29, no. 11, pp. 781–794, 2018. View at: Publisher Site | Google Scholar
  56. R. A. Vogel, M. C. Corretti, and G. D. Plotnick, “Effect of a single high-fat meal on endothelial function in healthy subjects,” The American Journal of Cardiology, vol. 79, no. 3, pp. 350–354, 1997. View at: Publisher Site | Google Scholar
  57. M. E. Tushuizen, R. Nieuwland, P. G. Scheffer, A. Sturk, R. J. Heine, and M. Diamant, “Two consecutive high-fat meals affect endothelial-dependent vasodilation, oxidative stress and cellular microparticles in healthy men,” Journal of Thrombosis and Haemostasis, vol. 4, no. 5, pp. 1003–1010, 2006. View at: Publisher Site | Google Scholar
  58. R. Kobayasi, E. H. Akamine, A. P. Davel, M. A. M. Rodrigues, C. R. O. Carvalho, and L. V. Rossoni, “Oxidative stress and inflammatory mediators contribute to endothelial dysfunction in high-fat diet-induced obesity in mice,” Journal of Hypertension, vol. 28, no. 10, pp. 2111–2119, 2010. View at: Publisher Site | Google Scholar
  59. R. De Caterina, J. K. Liao, and P. Libby, “Fatty acid modulation of endothelial activation,” The American Journal of Clinical Nutrition, vol. 71, no. 1, pp. 213S–223S, 2000. View at: Publisher Site | Google Scholar
  60. C. A. Dow, B. L. Stauffer, J. J. Greiner, and C. A. DeSouza, “Influence of dietary saturated fat intake on endothelial fibrinolytic capacity in adults,” The American Journal of Cardiology, vol. 114, no. 5, pp. 783–788, 2014. View at: Publisher Site | Google Scholar
  61. R. T. Gerber, K. Holemans, I. O'Brien-Coker et al., “Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat,” The Journal of Physiology, vol. 517, no. 2, pp. 607–616, 1999. View at: Publisher Site | Google Scholar
  62. E. A. Lambert, S. Phillips, R. Belski et al., “Endothelial function in healthy young individuals is associated with dietary consumption of saturated fat,” Frontiers in Physiology, vol. 8, p. 876, 2017. View at: Publisher Site | Google Scholar
  63. P. A. de Oliveira, C. Kovacs, P. Moreira, D. Magnoni, M. H. Saleh, and J. Faintuch, “Unsaturated fatty acids improve atherosclerosis markers in obese and overweight non-diabetic elderly patients,” Obesity Surgery, vol. 27, no. 10, pp. 2663–2671, 2017. View at: Publisher Site | Google Scholar
  64. V. D. S. Rocha, E. R. G. Claudio, V. L. da Silva et al., “High-fat diet-induced obesity model does not promote endothelial dysfunction via increasing Leptin/Akt/eNOS signaling,” Frontiers in Physiology, vol. 10, p. 268, 2019. View at: Publisher Site | Google Scholar
  65. E. Lopez-Garcia, M. B. Schulze, J. B. Meigs et al., “Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction,” The Journal of Nutrition, vol. 135, no. 3, pp. 562–566, 2005. View at: Publisher Site | Google Scholar
  66. N. M. de Roos, M. L. Bots, and M. B. Katan, “Replacement of dietary saturated fatty acids byTransFatty acids lowers serum HDL cholesterol and impairs endothelial function in healthy men and women,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 7, pp. 1233–1237, 2001. View at: Publisher Site | Google Scholar
  67. A. D. Lane-Cordova, J. R. Witmer, K. Dubishar et al., “High trans but not saturated fat beverage causes an acute reduction in postprandial vascular endothelial function but not arterial stiffness in humans,” Vascular Medicine, vol. 21, no. 5, pp. 429–436, 2016. View at: Publisher Site | Google Scholar
  68. N. G. Iwata, M. Pham, N. O. Rizzo, A. M. Cheng, E. Maloney, and F. Kim, “Trans fatty acids induce vascular inflammation and reduce vascular nitric oxide production in endothelial cells,” PLoS One, vol. 6, no. 12, article e29600, 2011. View at: Publisher Site | Google Scholar
  69. N. Zeeni, C. Dagher-Hamalian, H. Dimassi, and W. H. Faour, “Cafeteria diet-fed mice is a pertinent model of obesity-induced organ damage: a potential role of inflammation,” Inflammation Research, vol. 64, no. 7, pp. 501–512, 2015. View at: Publisher Site | Google Scholar
  70. B. P. Sampey, A. M. Vanhoose, H. M. Winfield et al., “Cafeteria diet is a robust model of human metabolic syndrome with liver and adipose inflammation: comparison to high-fat diet,” Obesity (Silver Spring), vol. 19, no. 6, pp. 1109–1117, 2011. View at: Publisher Site | Google Scholar
  71. P. Lang, S. Hasselwander, H. Li, and N. Xia, “Effects of different diets used in diet-induced obesity models on insulin resistance and vascular dysfunction in C57BL/6 mice,” Scientific Reports, vol. 9, no. 1, p. 19556, 2019. View at: Publisher Site | Google Scholar
  72. E. K. Naderali, L. C. Pickavance, J. P. H. Wilding, and G. Williams, “Diet-induced endothelial dysfunction in the rat is independent of the degree of increase in total body weight,” Clinical Science (London, England), vol. 100, no. 6, pp. 635–641, 2001. View at: Publisher Site | Google Scholar
  73. J. Carillon, B. Jover, J.-P. Cristol, J.-M. Rouanet, S. Richard, and A. Virsolvy, “Dietary supplementation with a specific melon concentrate reverses vascular dysfunction induced by cafeteria diet,” Food & Nutrition Research, vol. 60, no. 1, p. 32729, 2016. View at: Publisher Site | Google Scholar
  74. Q. Yang, Z. Zhang, E. W. Gregg, W. D. Flanders, R. Merritt, and F. B. Hu, “Added sugar intake and cardiovascular diseases mortality among US adults,” JAMA Internal Medicine, vol. 174, no. 4, pp. 516–524, 2014. View at: Publisher Site | Google Scholar
  75. L. A. Schmidt, “New unsweetened truths about sugar,” JAMA Internal Medicine, vol. 174, no. 4, pp. 525-526, 2014. View at: Publisher Site | Google Scholar
  76. C. M. O. Volpe, P. H. Villar-Delfino, P. M. F. Dos Anjos, and J. A. Nogueira-Machado, “Cellular death, reactive oxygen species (ROS) and diabetic complications,” Cell Death & Disease, vol. 9, no. 2, p. 119, 2018. View at: Publisher Site | Google Scholar
  77. J. H. Bae, E. Bassenge, K. B. Kim et al., “Postprandial hypertriglyceridemia impairs endothelial function by enhanced oxidant stress,” Atherosclerosis, vol. 155, no. 2, pp. 517–523, 2001. View at: Publisher Site | Google Scholar
  78. I. K. Lee, H. S. Kim, and J. H. Bae, “Endothelial dysfunction: its relationship with acute hyperglycaemia and hyperlipidemia,” International Journal of Clinical Practice. Supplement, vol. 129, pp. 59–64, 2002. View at: Google Scholar
  79. L. M. Title, P. M. Cummings, K. Giddens, and B. A. Nassar, “Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E,” Journal of the American College of Cardiology, vol. 36, no. 7, pp. 2185–2191, 2000. View at: Publisher Site | Google Scholar
  80. E. P. Weiss, H. Arif, D. T. Villareal, E. Marzetti, and J. O. Holloszy, “Endothelial function after high-sugar-food ingestion improves with endurance exercise performed on the previous day,” The American Journal of Clinical Nutrition, vol. 88, no. 1, pp. 51–57, 2008. View at: Publisher Site | Google Scholar
  81. F. de Souza Affonso, S. Cailleaux, L. F. C. Pinto, M. de Brito Gomes, and E. Tibiriçá, “Effects of high glucose concentrations on the endothelial function of the renal microcirculation of rabbits,” Arquivos Brasileiros de Cardiologia, vol. 81, no. 2, pp. 161–165, 2003. View at: Publisher Site | Google Scholar
  82. A. B. El-Remessy, G. Abou-Mohamed, R. W. Caldwell, and R. B. Caldwell, “High glucose-induced tyrosine nitration in endothelial cells: role of eNOS uncoupling and aldose reductase activation,” Investigative Ophthalmology & Visual Science, vol. 44, no. 7, pp. 3135–3143, 2003. View at: Publisher Site | Google Scholar
  83. W. Cai, J. Li, J. Shi et al., “Acute metabolic and endocrine responses induced by glucose and fructose in healthy young subjects: a double-blinded, randomized, crossover trial,” Clinical Nutrition, vol. 37, no. 2, pp. 459–470, 2018. View at: Publisher Site | Google Scholar
  84. M. Aragno and R. Mastrocola, “Dietary sugars and endogenous formation of advanced glycation endproducts: emerging mechanisms of disease,” Nutrients, vol. 9, no. 4, p. 385, 2017. View at: Publisher Site | Google Scholar
  85. A. Stirban, M. Negrean, C. Götting et al., “Dietary advanced glycation endproducts and oxidative Stress,” Annals of the New York Academy of Sciences, vol. 1126, no. 1, pp. 276–279, 2008. View at: Publisher Site | Google Scholar
  86. A. Stirban, M. Negrean, B. Stratmann et al., “Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes,” Diabetes Care, vol. 29, no. 9, pp. 2064–2071, 2006. View at: Publisher Site | Google Scholar
  87. N. Ahmed, “Advanced glycation endproducts--role in pathology of diabetic complications,” Diabetes Research and Clinical Practice, vol. 67, no. 1, pp. 3–21, 2005. View at: Publisher Site | Google Scholar
  88. H. Vlassara and J. Uribarri, “Glycoxidation and diabetic complications: modern lessons and a warning?” Reviews in Endocrine & Metabolic Disorders, vol. 5, no. 3, pp. 181–188, 2004. View at: Publisher Site | Google Scholar
  89. H. Vlassara, W. Cai, J. Crandall et al., “Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 24, pp. 15596–15601, 2002. View at: Publisher Site | Google Scholar
  90. Y. Du, A. Kowluru, and T. S. Kern, “PP2A contributes to endothelial death in high glucose: inhibition by benfotiamine,” American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, vol. 299, no. 6, pp. R1610–R1617, 2010. View at: Publisher Site | Google Scholar
  91. T. P. Keeley, R. C. M. Siow, R. Jacob, and G. E. Mann, “A PP2A-mediated feedback mechanism controls Ca2+‐dependent NO synthesis under physiological oxygen,” The FASEB Journal, vol. 31, no. 12, pp. 5172–5183, 2017. View at: Publisher Site | Google Scholar
  92. E. R. Galimov, “The role of p66shc in oxidative stress and apoptosis,” Acta Naturae, vol. 2, no. 4, pp. 44–51, 2010. View at: Publisher Site | Google Scholar
  93. T. D. Swink, E. P. Vining, and J. M. Freeman, “The ketogenic diet: 1997,” Advances in Pediatrics, vol. 44, pp. 297–329, 1997. View at: Google Scholar
  94. J. M. Freeman, J. B. Freeman, and M. T. Kelly, The Ketogenic Diet: a Treatment for Epilepsy, Demos Medical Publishing, 2000.
  95. B. Moreno, D. Bellido, I. Sajoux et al., “Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity,” Endocrine, vol. 47, no. 3, pp. 793–805, 2014. View at: Publisher Site | Google Scholar
  96. N. Steckhan, C. D. Hohmann, C. Kessler, G. Dobos, A. Michalsen, and H. Cramer, “Effects of different dietary approaches on inflammatory markers in patients with metabolic syndrome: a systematic review and meta-analysis,” Nutrition, vol. 32, no. 3, pp. 338–348, 2016. View at: Publisher Site | Google Scholar
  97. T. D. Noakes and J. Windt, “Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review,” British Journal of Sports Medicine, vol. 51, no. 2, pp. 133–139, 2017. View at: Publisher Site | Google Scholar
  98. C. Kosinski and F. R. Jornayvaz, “Effects of ketogenic diets on cardiovascular risk factors: evidence from animal and human studies,” Nutrients, vol. 9, no. 5, p. 517, 2017. View at: Publisher Site | Google Scholar
  99. F. F. Samaha, N. Iqbal, P. Seshadri et al., “A low-carbohydrate as compared with a low-fat diet in severe obesity,” New England Journal of Medicine, vol. 348, no. 21, pp. 2074–2081, 2003. View at: Publisher Site | Google Scholar
  100. F. Prattichizzo, V. de Nigris, S. Micheloni, L. la Sala, and A. Ceriello, “Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: is low-grade inflammation the neglected component?” Obesity and Metabolism, vol. 20, no. 11, pp. 2515–2522, 2018. View at: Publisher Site | Google Scholar
  101. E. Meroni, N. Papini, F. Criscuoli et al., “Metabolic responses in endothelial cells following exposure to ketone bodies,” Nutrients, vol. 10, no. 2, p. 250, 2018. View at: Publisher Site | Google Scholar
  102. M. Jabs, A. J. Rose, L. H. Lehmann et al., “Inhibition of endothelial notch signaling impairs fatty acid transport and leads to metabolic and vascular remodeling of the adult heart,” Circulation, vol. 137, no. 24, pp. 2592–2608, 2018. View at: Publisher Site | Google Scholar
  103. S. Y. Foo, E. R. Heller, J. Wykrzykowska et al., “Vascular effects of a low-carbohydrate high-protein diet,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 36, pp. 15418–15423, 2009. View at: Publisher Site | Google Scholar
  104. P. Lagiou, S. Sandin, M. Lof, D. Trichopoulos, H. O. Adami, and E. Weiderpass, “Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study,” BMJ, vol. 344, no. jun26 3, article e4026, 2012. View at: Publisher Site | Google Scholar
  105. G. Coppola, F. Natale, A. Torino et al., “The impact of the ketogenic diet on arterial morphology and endothelial function in children and young adults with epilepsy: a case–control study,” Seizure, vol. 23, no. 4, pp. 260–265, 2014. View at: Publisher Site | Google Scholar
  106. T. D. Valsdottir, C. Henriksen, N. Odden et al., “Effect of a low-carbohydrate high-fat diet and a single bout of exercise on glucose tolerance, lipid profile and endothelial function in normal weight young healthy females,” Frontiers in Physiology, vol. 10, p. 1499, 2019. View at: Publisher Site | Google Scholar
  107. C. Durrer, N. Lewis, Z. Wan, P. Ainslie, N. Jenkins, and J. Little, “Short-term low-carbohydrate high-fat diet in healthy young males renders the endothelium susceptible to hyperglycemia-induced damage, an exploratory analysis,” Nutrients, vol. 11, no. 3, p. 489, 2019. View at: Publisher Site | Google Scholar
  108. M. J. Burkitt, “An overlooked danger of ketogenic diets Making the case that ketone bodies induce vascular damage by the same mechanisms as glucose,” Nutrition, vol. 75-76, article 110763, 2020. View at: Publisher Site | Google Scholar
  109. L. S. Rallidis, J. Lekakis, A. Kolomvotsou et al., “Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity,” The American Journal of Clinical Nutrition, vol. 90, no. 2, pp. 263–268, 2009. View at: Publisher Site | Google Scholar
  110. M. Fito and V. Konstantinidou, “Nutritional genomics and the Mediterranean diet’s effects on human cardiovascular health,” Nutrients, vol. 8, no. 4, p. 218, 2016. View at: Publisher Site | Google Scholar
  111. A. Tuttolomondo, I. Simonetta, M. Daidone, A. Mogavero, A. Ortello, and A. Pinto, “Metabolic and vascular effect of the Mediterranean diet,” International Journal of Molecular Sciences, vol. 20, no. 19, p. 4716, 2019. View at: Publisher Site | Google Scholar
  112. J. Merino, R. Kones, and E. Ros, “Effects of Mediterranean diet on endothelial function,” in Endothelium and Cardiovascular Diseases, pp. 363–389, Elsevier, 2018. View at: Google Scholar
  113. C. E. Storniolo, R. Casillas, M. Bulló et al., “A Mediterranean diet supplemented with extra virgin olive oil or nuts improves endothelial markers involved in blood pressure control in hypertensive women,” European Journal of Nutrition, vol. 56, no. 1, pp. 89–97, 2017. View at: Publisher Site | Google Scholar
  114. C. Marin, R. Ramirez, J. Delgado-Lista et al., “Mediterranean diet reduces endothelial damage and improves the regenerative capacity of endothelium,” The American Journal of Clinical Nutrition, vol. 93, no. 2, pp. 267–274, 2011. View at: Publisher Site | Google Scholar
  115. M. Fitó, M. Guxens, D. Corella et al., “Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial,” Archives of Internal Medicine, vol. 167, no. 11, pp. 1195–1203, 2007. View at: Publisher Site | Google Scholar
  116. C. Marin, J. Delgado-Lista, R. Ramirez et al., “Mediterranean diet reduces senescence-associated stress in endothelial cells,” Age, vol. 34, no. 6, pp. 1309–1316, 2012. View at: Publisher Site | Google Scholar
  117. A. Ambring, P. Friberg, M. Axelsen et al., “Effects of a Mediterranean-inspired diet on blood lipids, vascular function and oxidative stress in healthy subjects,” Clinical Science, vol. 106, no. 5, pp. 519–525, 2004. View at: Publisher Site | Google Scholar
  118. R. Moreno-Luna, R. Muñoz-Hernandez, M. L. Miranda et al., “Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension,” American Journal of Hypertension, vol. 25, no. 12, pp. 1299–1304, 2012. View at: Publisher Site | Google Scholar
  119. N. Xia, C. Schirra, S. Hasselwander, U. Förstermann, and H. Li, “Red fruit (Pandanus conoideus Lam) oil stimulates nitric oxide production and reduces oxidative stress in endothelial cells,” Journal of Functional Foods, vol. 51, pp. 65–74, 2018. View at: Publisher Site | Google Scholar
  120. M. Das, I. Gabriely, and N. Barzilai, “Caloric restriction, body fat and ageing in experimental models,” Obesity Reviews, vol. 5, no. 1, pp. 13–19, 2004. View at: Publisher Site | Google Scholar
  121. R. Weindruch, M. A. Lane, D. K. Ingram, W. B. Ershler, and G. S. Roth, “Dietary restriction in rhesus monkeys: lymphopenia and reduced mitogen-induced proliferation in peripheral blood mononuclear cells,” Aging (Milano), vol. 9, no. 4, pp. 304–308, 1997. View at: Publisher Site | Google Scholar
  122. A. J. Donato, D. R. Machin, and L. A. Lesniewski, “Mechanisms of dysfunction in the aging vasculature and role in age-related disease,” Circulation Research, vol. 123, no. 7, pp. 825–848, 2018. View at: Publisher Site | Google Scholar
  123. L. Fontana, “Calorie restriction and cardiometabolic health,” European Journal of Cardiovascular Prevention and Rehabilitation, vol. 15, no. 1, pp. 3–9, 2008. View at: Publisher Site | Google Scholar
  124. M. Zanetti, G. G. Cappellari, I. Burekovic, R. Barazzoni, M. Stebel, and G. Guarnieri, “Caloric restriction improves endothelial dysfunction during vascular aging: effects on nitric oxide synthase isoforms and oxidative stress in rat aorta,” Experimental Gerontology, vol. 45, no. 11, pp. 848–855, 2010. View at: Publisher Site | Google Scholar
  125. C. Rippe, L. Lesniewski, M. Connell, T. LaRocca, A. Donato, and D. Seals, “Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress,” Aging Cell, vol. 9, no. 3, pp. 304–312, 2010. View at: Publisher Site | Google Scholar
  126. I. Mattagajasingh, C. S. Kim, A. Naqvi et al., “SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 37, pp. 14855–14860, 2007. View at: Publisher Site | Google Scholar
  127. M. Zanetti, R. Barazzoni, M. Vadori, M. Stebel, G. Biolo, and G. Guarnieri, “Lack of direct effect of moderate hyperleptinemia to improve endothelial function in lean rat aorta: role of calorie restriction,” Atherosclerosis, vol. 175, no. 2, pp. 253–259, 2004. View at: Publisher Site | Google Scholar
  128. L. Fontana, T. E. Meyer, S. Klein, and J. O. Holloszy, “Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 17, pp. 6659–6663, 2004. View at: Publisher Site | Google Scholar
  129. Z. Ungvari, C. Parrado-Fernandez, A. Csiszar, and R. de Cabo, “Mechanisms underlying caloric restriction and lifespan regulation: implications for vascular aging,” Circulation Research, vol. 102, no. 5, pp. 519–528, 2008. View at: Publisher Site | Google Scholar
  130. A. W. C. Man, H. Li, and N. Xia, “The role of Sirtuin 1 in regulating endothelial function, arterial remodeling and vascular aging,” Frontiers in Physiology, vol. 10, p. 1173, 2019. View at: Google Scholar
  131. A. Csiszar, N. Labinskyy, J. T. Pinto et al., “Resveratrol induces mitochondrial biogenesis in endothelial cells,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 297, no. 1, pp. H13–H20, 2009. View at: Publisher Site | Google Scholar
  132. V. W. Dolinsky and J. R. Dyck, “Calorie restriction and resveratrol in cardiovascular health and disease,” Biochimica et Biophysica Acta, vol. 1812, no. 11, pp. 1477–1489, 2011. View at: Publisher Site | Google Scholar
  133. D. W. Belsky, K. M. Huffman, C. F. Pieper, I. Shalev, and W. E. Kraus, “Change in the rate of biological aging in response to caloric restriction: CALERIE Biobank analysis,” The Journals of Gerontology: Series A, vol. 73, no. 1, pp. 4–10, 2017. View at: Google Scholar
  134. J. Most, L. A. Gilmore, S. R. Smith, H. Han, E. Ravussin, and L. M. Redman, “Significant improvement in cardiometabolic health in healthy nonobese individuals during caloric restriction-induced weight loss and weight loss maintenance,” American Journal of Physiology. Endocrinology and Metabolism, vol. 314, no. 4, pp. E396–E405, 2018. View at: Publisher Site | Google Scholar
  135. S. Sasaki, Y. Higashi, K. Nakagawa et al., “A low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension,” American Journal of Hypertension, vol. 15, no. 4, pp. 302–309, 2002. View at: Publisher Site | Google Scholar
  136. T. E. Meyer, S. J. Kovács, A. A. Ehsani, S. Klein, J. O. Holloszy, and L. Fontana, “Long-term caloric restriction ameliorates the decline in diastolic function in humans,” Journal of the American College of Cardiology, vol. 47, no. 2, pp. 398–402, 2006. View at: Publisher Site | Google Scholar
  137. M. C. Klempel, C. M. Kroeger, E. Norkeviciute, M. Goslawski, S. A. Phillips, and K. A. Varady, “Benefit of a low-fat over high-fat diet on vascular health during alternate day fasting,” Nutrition & Diabetes, vol. 3, no. 5, article e71, 2013. View at: Publisher Site | Google Scholar
  138. I. C. Arts and P. C. Hollman, “Polyphenols and disease risk in epidemiologic studies,” The American Journal of Clinical Nutrition, vol. 81, no. 1, pp. 317S–325S, 2005. View at: Publisher Site | Google Scholar
  139. M. T. Mitjavila and J. J. Moreno, “The effects of polyphenols on oxidative stress and the arachidonic acid cascade. Implications for the prevention/treatment of high prevalence diseases,” Biochemical Pharmacology, vol. 84, no. 9, pp. 1113–1122, 2012. View at: Publisher Site | Google Scholar
  140. G. Pounis, S. Costanzo, M. Bonaccio et al., “Reduced mortality risk by a polyphenol-rich diet: an analysis from the Moli-sani study,” Nutrition, vol. 48, pp. 87–95, 2018. View at: Publisher Site | Google Scholar
  141. D. Palmieri, B. Pane, C. Barisione et al., “Resveratrol counteracts systemic and local inflammation involved in early abdominal aortic aneurysm development,” The Journal of Surgical Research, vol. 171, no. 2, pp. e237–e246, 2011. View at: Publisher Site | Google Scholar
  142. J. A. Baur and D. A. Sinclair, “Therapeutic potential of resveratrol: the in vivo evidence,” Nature Reviews. Drug Discovery, vol. 5, no. 6, pp. 493–506, 2006. View at: Publisher Site | Google Scholar
  143. M. Jang, L. Cai, G. O. Udeani et al., “Cancer chemopreventive activity of resveratrol, a natural product derived from grapes,” Science, vol. 275, no. 5297, pp. 218–220, 1997. View at: Publisher Site | Google Scholar
  144. H. Li, N. Xia, S. Hasselwander, and A. Daiber, “Resveratrol and vascular function,” International Journal of Molecular Sciences, vol. 20, no. 9, p. 2155, 2019. View at: Publisher Site | Google Scholar
  145. N. Xia, A. Daiber, U. Förstermann, and H. Li, “Antioxidant effects of resveratrol in the cardiovascular system,” British Journal of Pharmacology, vol. 174, no. 12, pp. 1633–1646, 2017. View at: Publisher Site | Google Scholar
  146. P. E. Szmitko and S. Verma, “Cardiology patient pages. Red wine and your heart,” Circulation, vol. 111, no. 2, pp. e10–e11, 2005. View at: Publisher Site | Google Scholar
  147. R. Estruch, E. Sacanella, F. Mota et al., “Moderate consumption of red wine, but not gin, decreases erythrocyte superoxide dismutase activity: a randomised cross-over trial,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 21, no. 1, pp. 46–53, 2011. View at: Publisher Site | Google Scholar
  148. R. D. Pino-García, M. D. Rivero-Pérez, M. L. González-SanJosé, K. D. Croft, and P. Muñiz, “Antihypertensive and antioxidant effects of supplementation with red wine pomace in spontaneously hypertensive rats,” Food & Function, vol. 8, no. 7, pp. 2444–2454, 2017. View at: Publisher Site | Google Scholar
  149. P. L. da Luz, D. Favarato, and O. Berwanger, Action of Red Wine and Polyphenols upon Endothelial Function and Clinical Events, in Endothelium and Cardiovascular Diseases, Elsevier, 2018.
  150. I. P. G. Botden, J. G. Langendonk, M. E. Meima et al., “Daily red wine consumption improves vascular function by a soluble guanylyl cyclase-dependent pathway,” American Journal of Hypertension, vol. 24, no. 2, pp. 162–168, 2011. View at: Publisher Site | Google Scholar
  151. K. Suzuki, M. S. V. Elkind, B. Boden-Albala et al., “Moderate alcohol consumption is associated with better endothelial function: a cross sectional study,” BMC Cardiovascular Disorders, vol. 9, no. 1, p. 8, 2009. View at: Publisher Site | Google Scholar
  152. L. Liberale, A. Bonaventura, F. Montecucco, F. Dallegri, and F. Carbone, “Impact of red wine consumption on cardiovascular health,” Current Medicinal Chemistry, vol. 26, no. 19, pp. 3542–3566, 2019. View at: Publisher Site | Google Scholar
  153. T. O. Kiviniemi, A. Saraste, J. O. Toikka et al., “A moderate dose of red wine, but not de-alcoholized red wine increases coronary flow reserve,” Atherosclerosis, vol. 195, no. 2, pp. e176–e181, 2007. View at: Publisher Site | Google Scholar
  154. D. Tousoulis, I. Ntarladimas, C. Antoniades et al., “Acute effects of different alcoholic beverages on vascular endothelium, inflammatory markers and thrombosis fibrinolysis system,” Clinical Nutrition, vol. 27, no. 4, pp. 594–600, 2008. View at: Publisher Site | Google Scholar
  155. B. C. T. van Bussel, R. M. A. Henry, C. G. Schalkwijk et al., “Alcohol and red wine consumption, but not fruit, vegetables, fish or dairy products, are associated with less endothelial dysfunction and less low-grade inflammation: the Hoorn Study,” European Journal of Nutrition, vol. 57, no. 4, pp. 1409–1419, 2018. View at: Publisher Site | Google Scholar
  156. S. Vasdev, C. A. Ford, L. Longerich, S. Parai, and V. Gadag, “Antihypertensive effect of low ethanol intake in spontaneously hypertensive rats,” Molecular and Cellular Biochemistry, vol. 200, no. 1/2, pp. 85–92, 1999. View at: Publisher Site | Google Scholar
  157. Agriculture, USDoHaHSaUSDo, 2015 – 2020 Dietary Guidelines for Americans, U.S. Department of Agriculture and HHS, 2015.
  158. C. R. W. Kuhlmann, F. Li, D. W. Lüdders et al., “Dose-dependent activation of Ca2+-activated K+ channels by ethanol contributes to improved endothelial cell functions,” Alcoholism-Clinical and Experimental Research, vol. 28, no. 7, pp. 1005–1011, 2004. View at: Publisher Site | Google Scholar
  159. J. Liu, Z. Tian, B. Gao, and G. Kunos, “Dose-dependent activation of antiapoptotic and proapoptotic pathways by ethanol treatment in human vascular endothelial cells: differential involvement of adenosine.,” The Journal of Biological Chemistry, vol. 277, no. 23, pp. 20927–20933, 2002. View at: Publisher Site | Google Scholar
  160. J. A. Polikandriotis, H. L. Rupnow, and C. M. Hart, “Chronic ethanol exposure stimulates endothelial cell nitric oxide production through PI-3 Kinase-and hsp90-dependent mechanisms,” Alcoholism-Clinical and Experimental Research, vol. 29, no. 11, pp. 1932–1938, 2005. View at: Publisher Site | Google Scholar
  161. N. Oda, M. Kajikawa, T. Maruhashi et al., “Endothelial function is impaired in relation to alcohol intake even in the case of light alcohol consumption in Asian men; Flow-mediated Dilation Japan (FMD-J) Study,” International Journal of Cardiology, vol. 230, pp. 523–528, 2017. View at: Publisher Site | Google Scholar
  162. J. H. O'Keefe, J. J. DiNicolantonio, and C. J. Lavie, “Coffee for cardioprotection and longevity,” Progress in Cardiovascular Diseases, vol. 61, no. 1, pp. 38–42, 2018. View at: Publisher Site | Google Scholar
  163. M. Woodward and H. Tunstall-Pedoe, “Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality,” Journal of Epidemiology and Community Health, vol. 53, no. 8, pp. 481–487, 1999. View at: Publisher Site | Google Scholar
  164. R. M. van Dam and E. J. Feskens, “Coffee consumption and risk of type 2 diabetes mellitus,” The Lancet, vol. 360, no. 9344, pp. 1477-1478, 2002. View at: Publisher Site | Google Scholar
  165. A. Hino, H. Adachi, M. Enomoto et al., “Habitual coffee but not green tea consumption is inversely associated with metabolic syndrome,” Diabetes Research and Clinical Practice, vol. 76, no. 3, pp. 383–389, 2007. View at: Publisher Site | Google Scholar
  166. M. Ding, S. N. Bhupathiraju, A. Satija, R. M. van Dam, and F. B. Hu, “Long-term coffee consumption and risk of cardiovascular disease a systematic review and a dose-response meta-analysis of prospective cohort studies,” Circulation, vol. 129, no. 6, pp. 643–659, 2014. View at: Publisher Site | Google Scholar
  167. G. Siasos, D. Tousoulis, and C. Stefanadis, “Effects of habitual coffee consumption on vascular function,” Journal of the American College of Cardiology, vol. 63, no. 6, pp. 606-607, 2014. View at: Publisher Site | Google Scholar
  168. E. A. J. Boon, K. D. Croft, S. Shinde, J. M. Hodgson, and N. C. Ward, “The acute effect of coffee on endothelial function and glucose metabolism following a glucose load in healthy human volunteers,” Food & Function, vol. 8, no. 9, pp. 3366–3373, 2017. View at: Publisher Site | Google Scholar
  169. T. Umemura, K. Ueda, K. Nishioka et al., “Effects of acute administration of caffeine on vascular function,” The American Journal of Cardiology, vol. 98, no. 11, pp. 1538–1541, 2006. View at: Publisher Site | Google Scholar
  170. J. Vinson, K. Patel, and G. Agbor, “Polyphenols: total amounts in foods and beverages and US per capital consumption. ACS 230th National Meeting,” in Book of abstracts (n. AGFD 10), American Chemical Society, Washington, 2005. View at: Google Scholar
  171. F. Natella, M. Nardini, I. Giannetti, C. Dattilo, and C. Scaccini, “Coffee drinking influences plasma antioxidant capacity in humans,” Journal of Agricultural and Food Chemistry, vol. 50, no. 21, pp. 6211–6216, 2002. View at: Publisher Site | Google Scholar
  172. D. Martini, C. del Bo’, M. Tassotti et al., “Coffee consumption and oxidative stress: a review of human intervention studies,” Molecules, vol. 21, no. 8, p. 979, 2016. View at: Publisher Site | Google Scholar
  173. I. Spyridopoulos, S. Fichtlscherer, R.̈. Popp et al., “Caffeine enhances endothelial repair by an AMPK-dependent mechanism,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, pp. 1967–1974, 2008. View at: Publisher Site | Google Scholar
  174. R. Jiang, J. M. Hodgson, E. Mas, K. D. Croft, and N. C. Ward, “Chlorogenic acid improves ex vivo vessel function and protects endothelial cells against HOCl-induced oxidative damage, via increased production of nitric oxide and induction of Hmox-1,” The Journal of Nutritional Biochemistry, vol. 27, pp. 53–60, 2016. View at: Publisher Site | Google Scholar
  175. C. . M. Papamichael, K. . A. Aznaouridis, E. . N. Karatzis et al., “Effect of coffee on endothelial function in healthy subjects: the role of caffeine,” Clinical Science (London, England), vol. 109, no. 1, pp. 55–60, 2005. View at: Publisher Site | Google Scholar
  176. A. Fasano, “Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer,” Physiological Reviews, vol. 91, no. 1, pp. 151–175, 2011. View at: Publisher Site | Google Scholar
  177. R. E. Kleinman, O.-J. Goulet, G. Mieli-Vergani, I. R. Sanderson, P. M. Sherman, and B. L. Shneider, Walker’s Pediatric Gastrointestinal Disease: Physiology, Diagnosis, Management, BC Decker INC, Hamilton, 2008.
  178. Y. Matsuzawa and A. Lerman, “Endothelial dysfunction and coronary artery disease: assessment, prognosis, and treatment,” Coronary Artery Disease, vol. 25, no. 8, pp. 713–724, 2014. View at: Publisher Site | Google Scholar
  179. A. Comba, G. Çaltepe, K. Yanık, U. Gör, Ö. Yüce, and A. G. Kalaycı, “Assessment of endothelial dysfunction with adhesion molecules in patients with celiac disease,” Journal of Pediatric Gastroenterology and Nutrition, vol. 63, no. 2, pp. 247–252, 2016. View at: Publisher Site | Google Scholar
  180. J. Diaz-Castro, C. Muriel-Neyra, R. Martin-Masot, J. Moreno-Fernandez, J. Maldonado, and T. Nestares, “Oxidative stress, DNA stability and evoked inflammatory signaling in young celiac patients consuming a gluten-free diet,” European Journal of Nutrition, vol. 59, no. 4, pp. 1577–1584, 2020. View at: Publisher Site | Google Scholar
  181. V. F. Zevallos, V. Raker, S. Tenzer et al., “Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells,” Gastroenterology, vol. 152, no. 5, pp. 1100–1113.e12, 2017, e12. View at: Publisher Site | Google Scholar
  182. V. F. Zevallos, J. McCarville, A. C. Fernandez, E. F. Verdu, and D. Schuppan, “Microbial modulation of intestinal innate activation triggered by wheat amylase trypsin inhibitors (ATIS) in NOD-DQ8 mice,” Gastroenterology, vol. 152, no. 5, p. S71, 2017. View at: Publisher Site | Google Scholar
  183. V. Zevallos, J. Weinmann-Menke, M. Meineck, and D. Schuppan, “Disease progression in murine systemic lupus erythematosus induced by consumption of amylase trypsin inhibitor (ATIs),” Zeitschrift für Gastroenterologie, vol. 54, no. 8, 2016. View at: Publisher Site | Google Scholar
  184. J. Jamnik, B. García-Bailo, C. H. Borchers, and A. el-Sohemy, “Gluten intake is positively associated with plasma α2-macroglobulin in young adults,” The Journal of Nutrition, vol. 145, no. 6, pp. 1256–1262, 2015. View at: Publisher Site | Google Scholar
  185. E. C. Aguilar, J. M. Navia-Pelaez, W. Fernandes-Braga et al., “Gluten exacerbates atherosclerotic plaque formation in ApoE mice with diet-induced obesity,” Nutrition, vol. 75-76, article 110658, 2019. View at: Google Scholar
  186. L. Loffredo, L. Perri, E. Catasca et al., “Dark chocolate acutely improves walking autonomy in patients with peripheral artery disease,” Journal of the American Heart Association, vol. 3, no. 4, 2014. View at: Publisher Site | Google Scholar
  187. D. Grassi, G. Desideri, and C. Ferri, “Flavonoids: antioxidants against atherosclerosis,” Nutrients, vol. 2, no. 8, pp. 889–902, 2010. View at: Publisher Site | Google Scholar
  188. D. Grassi, G. Desideri, G. Croce, S. Tiberti, A. Aggio, and C. Ferri, “Flavonoids, vascular function and cardiovascular protection,” Current Pharmaceutical Design, vol. 15, no. 10, pp. 1072–1084, 2009. View at: Publisher Site | Google Scholar
  189. M. Gómez-Juaristi, L. González-Torres, L. Bravo, M. P. Vaquero, S. Bastida, and F. J. Sánchez-Muniz, “Beneficial effects of chocolate on cardiovascular health,” Nutrición Hospitalaria, vol. 26, no. 2, pp. 289–292, 2011. View at: Publisher Site | Google Scholar
  190. J. Balzer, T. Rassaf, C. Heiss et al., “Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial,” Journal of the American College of Cardiology, vol. 51, no. 22, pp. 2141–2149, 2008. View at: Publisher Site | Google Scholar
  191. D. Rein, S. Lotito, R. R. Holt, C. L. Keen, H. H. Schmitz, and C. G. Fraga, “Epicatechin in human plasma: in vivo determination and effect of chocolate consumption on plasma oxidation status,” The Journal of Nutrition, vol. 130, no. 8, pp. 2109S–2114S, 2000. View at: Publisher Site | Google Scholar
  192. Z. Zhang, G. Xu, and X. Liu, “Chocolate intake reduces risk of cardiovascular disease: evidence from 10 observational studies,” International Journal of Cardiology, vol. 168, no. 6, pp. 5448–5450, 2013. View at: Publisher Site | Google Scholar
  193. L. Loffredo, R. Carnevale, L. Perri et al., “NOX2-mediated arterial dysfunction in smokers: acute effect of dark chocolate,” Heart, vol. 97, no. 21, pp. 1776–1781, 2011. View at: Publisher Site | Google Scholar
  194. R. Carnevale, L. Loffredo, P. Pignatelli et al., “Dark chocolate inhibits platelet isoprostanes via NOX2 down-regulation in smokers,” Journal of Thrombosis and Haemostasis, vol. 10, no. 1, pp. 125–132, 2012. View at: Publisher Site | Google Scholar
  195. L. Loffredo, F. Baratta, P. Ludovica et al., “Effects of dark chocolate on endothelial function in patients with non-alcoholic steatohepatitis,” Nutrition, Metabolism, and Cardiovascular Diseases, vol. 28, no. 2, pp. 143–149, 2017. View at: Google Scholar
  196. Z. Faridi, V. Y. Njike, S. Dutta, A. Ali, and D. L. Katz, “Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial,” The American Journal of Clinical Nutrition, vol. 88, no. 1, pp. 58–63, 2008. View at: Publisher Site | Google Scholar
  197. J. Dyerberg and H. O. Bang, “Lipid metabolism, atherogenesis, and haemostasis in Eskimos: the role of the prostaglandin-3 family,” Haemostasis, vol. 8, no. 3-5, pp. 227–233, 1979. View at: Publisher Site | Google Scholar
  198. J. Dyerberg and H. O. Bang, “Haemostatic function and platelet polyunsaturated fatty acids in Eskimos,” The Lancet, vol. 2, no. 8140, pp. 433–435, 1979. View at: Google Scholar
  199. M. Weech, H. Altowaijri, J. Mayneris-Perxachs et al., “Replacement of dietary saturated fat with unsaturated fats increases numbers of circulating endothelial progenitor cells and decreases numbers of microparticles: findings from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study,” The American Journal of Clinical Nutrition, vol. 107, no. 6, pp. 876–882, 2018. View at: Publisher Site | Google Scholar
  200. Y. Adkins and D. S. Kelley, “Mechanisms underlying the cardioprotective effects of omega-3 polyunsaturated fatty acids,” The Journal of Nutritional Biochemistry, vol. 21, no. 9, pp. 781–792, 2010. View at: Publisher Site | Google Scholar
  201. P. L. Turcotte, A. Carrier, J. Desrosiers, and M. Levasseur, “Are health promotion and prevention interventions integrated into occupational therapy practice with older adults having disabilities? Insights from six community health settings in Québec, Canada,” Australian Occupational Therapy Journal, vol. 62, no. 1, pp. 56–67, 2015. View at: Publisher Site | Google Scholar
  202. J. Layne, Z. Majkova, E. J. Smart, M. Toborek, and B. Hennig, “Caveolae: a regulatory platform for nutritional modulation of inflammatory diseases,” The Journal of Nutritional Biochemistry, vol. 22, no. 9, pp. 807–811, 2011. View at: Publisher Site | Google Scholar
  203. O. Feron, C. Dessy, S. Moniotte, J. P. Desager, and J. L. Balligand, “Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase,” The Journal of Clinical Investigation, vol. 103, no. 6, pp. 897–905, 1999. View at: Publisher Site | Google Scholar
  204. M. Zanetti, A. Grillo, P. Losurdo et al., “ω-3 polyunsaturated fatty acids: structural and functional effects on the vascular wall,” BioMed Research International, vol. 2015, Article ID 791978, 14 pages, 2015. View at: Google Scholar
  205. Y. Wu, C. Zhang, Y. Dong et al., “Activation of the AMP-activated protein kinase by eicosapentaenoic acid (EPA, 20: 5 n-3) improves endothelial function in vivo,” PLoS One, vol. 7, no. 4, article e35508, 2012. View at: Publisher Site | Google Scholar
  206. G. G. Cappellari, P. Losurdo, S. Mazzucco et al., “Treatment with n-3 polyunsaturated fatty acids reverses endothelial dysfunction and oxidative stress in experimental menopause,” The Journal of Nutritional Biochemistry, vol. 24, no. 1, pp. 371–379, 2013. View at: Publisher Site | Google Scholar
  207. M. Nyby, K. Matsumoto, K. Yamamoto et al., “Dietary fish oil prevents vascular dysfunction and oxidative stress in hyperinsulinemic rats,” American Journal of Hypertension, vol. 18, no. 2, pp. 213–219, 2005. View at: Publisher Site | Google Scholar
  208. T. Matsumoto, N. Nakayama, K. Ishida, T. Kobayashi, and K. Kamata, “Eicosapentaenoic acid improves imbalance between vasodilator and vasoconstrictor actions of endothelium-derived factors in mesenteric arteries from rats at chronic stage of type 2 diabetes,” Journal of Pharmacology and Experimental Therapeutics, vol. 329, no. 1, pp. 324–334, 2009. View at: Publisher Site | Google Scholar
  209. L. Bo, S. Jiang, Y. Xie, H. Kan, W. Song, and J. Zhao, “Effect of vitamin E and omega-3 fatty acids on protecting ambient PM2.5-induced inflammatory response and oxidative stress in vascular endothelial cells,” PloS One, vol. 11, no. 3, article e0152216, 2016. View at: Publisher Site | Google Scholar
  210. C. Sakai, M. Ishida, H. Ohba et al., “Fish oil omega-3 polyunsaturated fatty acids attenuate oxidative stress-induced DNA damage in vascular endothelial cells,” PLoS One, vol. 12, no. 11, article e0187934, 2017. View at: Publisher Site | Google Scholar
  211. F. Thies, J. M. C. Garry, P. Yaqoob et al., “Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial,” The Lancet, vol. 361, no. 9356, pp. 477–485, 2003. View at: Publisher Site | Google Scholar
  212. M. L. Daviglus, J. Stamler, A. J. Orencia et al., “Fish consumption and the 30-year risk of fatal myocardial infarction,” The New England Journal of Medicine, vol. 336, no. 15, pp. 1046–1053, 1997. View at: Publisher Site | Google Scholar
  213. S. M. Felau, L. P. Sales, M. Y. Solis et al., “Omega-3 fatty acid supplementation improves endothelial function in primary antiphospholipid syndrome: a small-scale randomized double-blind placebo-controlled trial,” Frontiers in Immunology, vol. 9, p. 336, 2018. View at: Publisher Site | Google Scholar
  214. A. Stirban, S. Nandrean, C. Götting et al., “Effects of n-3 fatty acids on macro- and microvascular function in subjects with type 2 diabetes mellitus,” American Journal of Clinical Nutrition, vol. 91, no. 3, pp. 808–813, 2010. View at: Publisher Site | Google Scholar
  215. A. Hammer, D. Moertl, O. Schlager et al., “Effects ofn-3 PUFA on endothelial function in patients with peripheral arterial disease: a randomised, placebo-controlled, double-blind trial,” The British Journal of Nutrition, vol. 122, no. 6, pp. 698–706, 2019. View at: Publisher Site | Google Scholar
  216. E. Oikonomou, G. Vogiatzi, D. Karlis et al., “Effects of omega-3 polyunsaturated fatty acids on fibrosis, endothelial function and myocardial performance, in ischemic heart failure patients,” Clinical Nutrition, vol. 38, no. 3, pp. 1188–1197, 2019. View at: Publisher Site | Google Scholar
  217. M. A. Casanova, F. Medeiros, M. Trindade, C. Cohen, W. Oigman, and M. F. Neves, “Omega-3 fatty acids supplementation improves endothelial function and arterial stiffness in hypertensive patients with hypertriglyceridemia and high cardiovascular risk,” Journal of the American Society of Hypertension, vol. 11, no. 1, pp. 10–19, 2017. View at: Publisher Site | Google Scholar
  218. M. A. Farooq, S. Gaertner, L. Amoura et al., “Intake of omega-3 formulation EPA:DHA 6:1 by old rats for 2 weeks improved endothelium-dependent relaxations and normalized the expression level of ACE/AT1R/NADPH oxidase and the formation of ROS in the mesenteric artery,” Biochemical Pharmacology, vol. 173, p. 113749, 2020. View at: Publisher Site | Google Scholar
  219. A. Siniarski, M. Haberka, M. Mostowik et al., “Treatment with omega-3 polyunsaturated fatty acids does not improve endothelial function in patients with type 2 diabetes and very high cardiovascular risk: a randomized, double-blind, placebo-controlled study (omega-FMD),” Atherosclerosis, vol. 271, pp. 148–155, 2018. View at: Publisher Site | Google Scholar
  220. M. G. Traber and J. F. Stevens, “Vitamins C and E: beneficial effects from a mechanistic perspective,” Free Radical Biology & Medicine, vol. 51, no. 5, pp. 1000–1013, 2011. View at: Publisher Site | Google Scholar
  221. A. Jayedi, A. Rashidy-Pour, M. Parohan, M. S. Zargar, and S. Shab-Bidar, “Dietary and circulating vitamin C, vitamin E, β-carotene and risk of total cardiovascular mortality: a systematic review and dose-response meta-analysis of prospective observational studies,” Public Health Nutrition, vol. 22, no. 10, pp. 1872–1887, 2019. View at: Publisher Site | Google Scholar
  222. P. D. Tomo, R. Canali, D. Ciavardelli et al., “β-carotene and lycopene affect endothelial response to TNF-α reducing nitro-oxidative stress and interaction with monocytes,” Molecular Nutrition & Food Research, vol. 56, no. 2, pp. 217–227, 2012. View at: Publisher Site | Google Scholar
  223. H. Tapiero, “Influence of alcohol consumption and smoking habits on human health,” Biomedicine & Pharmacotherapy, vol. 58, no. 2, pp. 75-76, 2004. View at: Publisher Site | Google Scholar
  224. A. D'Odorico, D. Martines, S. Kiechl et al., “High plasma levels of alpha- and beta-carotene are associated with a lower risk of atherosclerosis: results from the Bruneck study,” Atherosclerosis, vol. 153, no. 1, pp. 231–239, 2000. View at: Publisher Site | Google Scholar
  225. K. F. Gey and P. Puska, “Plasma vitamins E and A inversely correlated to mortality from ischemic heart disease in cross-cultural epidemiology,” Annals of the New York Academy of Sciences, vol. 570, no. 1 Vitamin E, pp. 268–282, 1989. View at: Publisher Site | Google Scholar
  226. N. Di Pietro, P. Di Tomo, and A. Pandolfi, “Carotenoids in cardiovascular disease prevention,” JSM Atheroscler, vol. 1, no. 1, p. 1002, 2016. View at: Google Scholar
  227. J. A. Rodríguez, A. Grau, E. Eguinoa et al., “Dietary supplementation with vitamins C and E prevents downregulation of endothelial NOS expression in hypercholesterolemia in vivo and in vitro,” Atherosclerosis, vol. 165, no. 1, pp. 33–40, 2002. View at: Publisher Site | Google Scholar
  228. M. Shargorodsky, O. Debby, Z. Matas, and R. Zimlichman, “Effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors,” Nutrition & Metabolism (London), vol. 7, no. 1, p. 55, 2010. View at: Publisher Site | Google Scholar
  229. G. Ghaffari, M. Sabri, M. Hashemipour, N. Mostofizadeh, and A. M. Koushki, “Effect of long-term vitamin C intake on vascular endothelial function in diabetic children and adolescents: a pilot study,” Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, vol. 21, no. 1, p. 119, 2016. View at: Publisher Site | Google Scholar
  230. S. Dhein, A. Kabat, A. Olbrich, P. Rösen, H. Schröder, and F. W. Mohr, “Effect of chronic treatment with vitamin E on endothelial dysfunction in a type I in vivo diabetes mellitus model and in vitro,” The Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 1, pp. 114–122, 2003. View at: Publisher Site | Google Scholar
  231. Y. Plantinga, L. Ghiadoni, A. Magagna et al., “Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients,” American Journal of Hypertension, vol. 20, no. 4, pp. 392–397, 2007. View at: Publisher Site | Google Scholar
  232. A. Ceriello, A. Quatraro, and D. Giugliano, “New insights on non-enzymatic glycosylation may lead to therapeutic approaches for the prevention of diabetic complications,” Diabetic Medicine, vol. 9, no. 3, pp. 297–299, 1992. View at: Publisher Site | Google Scholar
  233. T. Y. Warren, V. Barry, S. P. Hooker, X. Sui, T. S. Church, and S. N. Blair, “Sedentary behaviors increase risk of cardiovascular disease mortality in men,” Medicine and Science in Sports and Exercise, vol. 42, no. 5, pp. 879–885, 2010. View at: Publisher Site | Google Scholar
  234. S. S. Anand, C. Hawkes, R. J. de Souza et al., “Food consumption and its impact on cardiovascular disease: importance of solutions focused on the globalized food system: a report from the workshop convened by the World Heart Federation,” Journal of the American College of Cardiology, vol. 66, no. 14, pp. 1590–1614, 2015. View at: Publisher Site | Google Scholar
  235. K. L. Piercy, R. P. Troiano, R. M. Ballard et al., “The physical activity guidelines for Americans,” JAMA, vol. 320, no. 19, pp. 2020–2028, 2018. View at: Publisher Site | Google Scholar
  236. R. S. Paffenbarger, J. B. Kampert, I. M. Lee, R. T. Hyde, R. W. Leung, and A. L. Wing, “Changes in physical activity and other lifeway patterns influencing longevity,” Medicine and Science in Sports and Exercise, vol. 26, no. 7, pp. 857–865, 1994. View at: Google Scholar
  237. D. C. Lee, X. Sui, E. G. Artero et al., “Long-term effects of changes in cardiorespiratory fitness and body mass index on all-cause and cardiovascular disease mortality in men: the Aerobics Center Longitudinal Study,” Circulation, vol. 124, no. 23, pp. 2483–2490, 2011. View at: Publisher Site | Google Scholar
  238. F. Giada, A. Biffi, P. Agostoni et al., “Exercise prescription for the prevention and treatment of cardiovascular diseases: part I,” Journal of Cardiovascular Medicine (Hagerstown, Md.), vol. 9, no. 5, pp. 529–544, 2008. View at: Publisher Site | Google Scholar
  239. M. H. Laughlin, R. J. Korthuis, D. J. Duncker, and R. J. Bache, Handbook of Physiology, Section 12, Exercise: Regulation and Integration of Multiple Systems, Oxford University Press Inc, 1996.
  240. J. E. Donnelly, S. N. Blair, J. M. Jakicic et al., “American College of Sports Medicine Position Stand. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults,” Medicine and Science in Sports and Exercise, vol. 41, no. 2, pp. 459–471, 2009. View at: Publisher Site | Google Scholar
  241. M. J. Gomes, L. U. Pagan, and M. P. Okoshi, “Non-pharmacological treatment of cardiovascular disease|importance of physical exercise,” Arquivos Brasileiros de Cardiologia, vol. 113, no. 1, pp. 9-10, 2019. View at: Publisher Site | Google Scholar
  242. J. Wang, M. S. Wolin, and T. H. Hintze, “Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs,” Circulation Research, vol. 73, no. 5, pp. 829–838, 1993. View at: Google Scholar
  243. J. Niebauer and J. P. Cooke, “Cardiovascular effects of exercise: role of endothelial shear stress,” Journal of the American College of Cardiology, vol. 28, no. 7, pp. 1652–1660, 1996. View at: Publisher Site | Google Scholar
  244. D. J. Green, A. Maiorana, G. O'Driscoll, and R. Taylor, “Effect of exercise training on endothelium-derived nitric oxide function in humans,” The Journal of Physiology, vol. 561, no. 1, pp. 1–25, 2004. View at: Publisher Site | Google Scholar
  245. R. Hambrecht, V. Adams, S. Erbs et al., “Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase,” Circulation, vol. 107, no. 25, pp. 3152–3158, 2003. View at: Publisher Site | Google Scholar
  246. T. M. Paravicini and R. M. Touyz, “Redox signaling in hypertension,” Cardiovascular Research, vol. 71, no. 2, pp. 247–258, 2006. View at: Publisher Site | Google Scholar
  247. Y. Higashi, “Exercise is a double-edged sword for endothelial function,” Hypertension Research, vol. 39, no. 2, pp. 61–63, 2016. View at: Publisher Site | Google Scholar
  248. M. T. Draney, R. J. Herfkens, T. J. R. Hughes et al., “Quantification of vessel wall cyclic strain using cine phase contrast magnetic resonance imaging,” Annals of Biomedical Engineering, vol. 30, no. 8, pp. 1033–1045, 2002. View at: Publisher Site | Google Scholar
  249. D. J. Green, M. T. E. Hopman, J. Padilla, M. H. Laughlin, and D. H. J. Thijssen, “Vascular adaptation to exercise in humans: role of hemodynamic stimuli,” Physiological Reviews, vol. 97, no. 2, pp. 495–528, 2017. View at: Publisher Site | Google Scholar
  250. M. H. Laughlin, S. C. Newcomer, and S. B. Bender, “Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype,” Journal of Applied Physiology, vol. 104, no. 3, pp. 588–600, 2008. View at: Publisher Site | Google Scholar
  251. V. J. Dzau, G. H. Gibbons, R. Morishita, and R. E. Pratt, “New perspectives in hypertension research. Potentials of vascular biology,” Hypertension, vol. 23, 6, Part 2, pp. 1132–1140, 1994. View at: Publisher Site | Google Scholar
  252. D. G. Harrison, J. Widder, I. Grumbach, W. Chen, M. Weber, and C. Searles, “Endothelial mechanotransduction, nitric oxide and vascular inflammation,” Journal of Internal Medicine, vol. 259, no. 4, pp. 351–363, 2006. View at: Publisher Site | Google Scholar
  253. L. L. Ji, “Antioxidants and oxidative stress in exercise,” Proceedings of the Society for Experimental Biology and Medicine, vol. 222, no. 3, pp. 283–292, 2003. View at: Google Scholar
  254. T. Fukai, M. R. Siegfried, M. Ushio-Fukai, Y. Cheng, G. Kojda, and D. G. Harrison, “Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training,” The Journal of Clinical Investigation, vol. 105, no. 11, pp. 1631–1639, 2000. View at: Publisher Site | Google Scholar
  255. L. L. Ji, “Exercise-induced modulation of antioxidant defense,” Annals of the New York Academy of Sciences, vol. 959, no. 1, pp. 82–92, 2002. View at: Publisher Site | Google Scholar
  256. R. T. Aejmelaeus, P. Holm, U. Kaukinen et al., “Age-related changes in the peroxyl radical scavenging capacity of human plasma,” Free Radical Biology & Medicine, vol. 23, no. 1, pp. 69–75, 1997. View at: Publisher Site | Google Scholar
  257. D. P. Jones, V. C. Mody Jr., J. L. Carlson, M. J. Lynn, and P. Sternberg Jr., “Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses,” Free Radical Biology & Medicine, vol. 33, no. 9, pp. 1290–1300, 2002. View at: Publisher Site | Google Scholar
  258. F. Franzoni, L. Ghiadoni, F. Galetta et al., “Physical activity, plasma antioxidant capacity, and endothelium-dependent vasodilation in young and older men,” American Journal of Hypertension, vol. 18, no. 4, pp. 510–516, 2005. View at: Publisher Site | Google Scholar
  259. A. W. Man and Y. Wang, “Age-associated arterial remodelling,” EC Cardiology, vol. 4, pp. 137–164, 2017. View at: Google Scholar
  260. R. D. Rudic and W. C. Sessa, “Nitric oxide in endothelial dysfunction and vascular remodeling: clinical correlates and experimental links,” American Journal of Human Genetics, vol. 64, no. 3, pp. 673–677, 1999. View at: Publisher Site | Google Scholar
  261. I. Hajj Hussein, W. Nourddine, N. Soudani, and A. Zeidan, “Nitric oxide inhibits vascular remodeling by decreasing angiotensin II-induced Rho A translocation to caveolae and ROS formation (867.6),” The FASEB Journal, vol. 28, Supplement 1, p. 867, 2014. View at: Google Scholar
  262. B. M. Prior, P. G. Lloyd, H. T. Yang, and R. L. Terjung, “Exercise-induced vascular remodeling,” Exercise and Sport Sciences Reviews, vol. 31, no. 1, pp. 26–33, 2003. View at: Publisher Site | Google Scholar
  263. M. M. Mota, T. L. T. B. D. Silva, F. N. Macedo et al., “Effects of a single bout of resistance exercise in different volumes on endothelium adaptations in healthy animals,” Arquivos Brasileiros de Cardiologia, vol. 108, no. 5, pp. 436–442, 2017. View at: Publisher Site | Google Scholar
  264. L. R. Johnson, J. W. E. Rush, J. R. Turk, E. M. Price, and M. H. Laughlin, “Short-term exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries,” Journal of Applied Physiology, vol. 90, no. 3, pp. 1102–1110, 2001. View at: Publisher Site | Google Scholar
  265. Z. Y. Ma and Y. C. Zhao, “Effects of aerobic exercise training on antihypertension and expressions of VEGF, eNOS of skeletal muscle in spontaneous hypertensive rats,” Zhongguo Ying Yong Sheng Li Xue Za Zhi, vol. 30, no. 4, pp. 320–324, 2014. View at: Google Scholar
  266. D. A. Graham and J. W. Rush, “Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats,” Journal of Applied Physiology, vol. 96, no. 6, pp. 2088–2096, 2004. View at: Publisher Site | Google Scholar
  267. F. T. de Oliveira, J. K. Angeli, L. G. M. Mello et al., “A single resistance exercise session improves aortic endothelial function in hypertensive rats,” Arquivos Brasileiros de Cardiologia, vol. 108, no. 3, pp. 228–236, 2017. View at: Google Scholar
  268. A. Minami, N. Ishimura, N. Harada, S. Sakamoto, Y. Niwa, and Y. Nakaya, “Exercise training improves acetylcholine-induced endothelium-dependent hyperpolarization in type 2 diabetic rats, Otsuka Long-Evans Tokushima fatty rats,” Atherosclerosis, vol. 162, no. 1, pp. 85–92, 2002. View at: Publisher Site | Google Scholar
  269. S. Sakamoto, K. Minami, Y. Niwa et al., “Effect of exercise training and food restriction on endothelium-dependent relaxation in the Otsuka Long-Evans Tokushima fatty rat, a model of spontaneous NIDDM,” Diabetes, vol. 47, no. 1, pp. 82–86, 1998. View at: Publisher Site | Google Scholar
  270. F. Moien-Afshari, S. Ghosh, S. Elmi et al., “Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice,” Diabetologia, vol. 51, no. 7, pp. 1327–1337, 2008. View at: Publisher Site | Google Scholar
  271. D. Sun, A. Huang, A. Koller, and G. Kaley, “Decreased arteriolar sensitivity to shear stress in adult rats is reversed by chronic exercise activity,” Microcirculation, vol. 9, no. 2, pp. 91–97, 2002. View at: Publisher Site | Google Scholar
  272. J. E. Martinez, E. F. Taipeiro, and A. B. Chies, “Effects of continuous and accumulated exercise on endothelial function in rat aorta,” Arquivos Brasileiros de Cardiologia, vol. 108, no. 4, pp. 315–322, 2017. View at: Publisher Site | Google Scholar
  273. S. A. Spier, M. D. Delp, C. J. Meininger, A. J. Donato, M. W. Ramsey, and J. M. Muller-Delp, “Effects of ageing and exercise training on endothelium-dependent vasodilatation and structure of rat skeletal muscle arterioles,” The Journal of Physiology, vol. 556, no. 3, pp. 947–958, 2004. View at: Publisher Site | Google Scholar
  274. K. Tsutsumi, M. Kusunoki, T. Hara et al., “Exercise improved accumulation of visceral fat and simultaneously impaired endothelium-dependent relaxation in old rats,” Biological & Pharmaceutical Bulletin, vol. 24, no. 1, pp. 88–91, 2001. View at: Publisher Site | Google Scholar
  275. X. Chen, X. An, D. Chen et al., “Chronic exercise training improved aortic endothelial and mitochondrial function via an AMPKalpha2-dependent manner,” Frontiers in Physiology, vol. 7, p. 631, 2016. View at: Google Scholar
  276. J. H. Lee, R. Lee, M. H. Hwang, M. T. Hamilton, and Y. Park, “The effects of exercise on vascular endothelial function in type 2 diabetes: a systematic review and meta-analysis,” Diabetology and Metabolic Syndrome, vol. 10, no. 1, p. 15, 2018. View at: Publisher Site | Google Scholar
  277. D. Chakraphan, P. Sridulyakul, B. Thipakorn, S. Bunnag, V. H. Huxley, and S. Patumraj, “Attenuation of endothelial dysfunction by exercise training in STZ-induced diabetic rats,” Clinical Hemorheology and Microcirculation, vol. 32, no. 3, pp. 217–226, 2005. View at: Google Scholar
  278. J. Hollander, R. Fiebig, M. Gore, T. Ookawara, H. Ohno, and L. Ji, “Superoxide dismutase gene expression is activated by a single bout of exercise in rat skeletal muscle,” Pflügers Archiv, vol. 442, no. 3, pp. 426–434, 2001. View at: Publisher Site | Google Scholar
  279. D. T. Beck, D. P. Casey, J. S. Martin, B. D. Emerson, and R. W. Braith, “Exercise training improves endothelial function in young prehypertensives,” Experimental Biology and Medicine (Maywood, N.J.), vol. 238, no. 4, pp. 433–441, 2013. View at: Publisher Site | Google Scholar
  280. D. T. Beck, J. S. Martin, D. P. Casey, and R. W. Braith, “Exercise training improves endothelial function in resistance arteries of young prehypertensives,” Journal of Human Hypertension, vol. 28, no. 5, pp. 303–309, 2014. View at: Publisher Site | Google Scholar
  281. M. L. Pedralli, R. A. Marschner, D. P. Kollet et al., “Different exercise training modalities produce similar endothelial function improvements in individuals with prehypertension or hypertension: a randomized clinical trial,” Scientific Reports, vol. 10, no. 1, p. 7628, 2020. View at: Publisher Site | Google Scholar
  282. P. R. Zaros, C. E. M. R. Pires, M. Bacci Jr., C. Moraes, and A. Zanesco, “Effect of 6-months of physical exercise on the nitrate/nitrite levels in hypertensive postmenopausal women,” BMC Womens Health, vol. 9, no. 1, p. 17, 2009. View at: Publisher Site | Google Scholar
  283. M. R. Bonsignore, G. Morici, L. Riccobono et al., “Airway inflammation in nonasthmatic amateur runners,” American Journal of Physiology. Lung Cellular and Molecular Physiology, vol. 281, no. 3, pp. L668–L676, 2001. View at: Publisher Site | Google Scholar
  284. K. J. Mantione, T. Esch, and G. B. Stefano, “Detection of nitric oxide in exhaled human breath: exercise and resting determinations,” Medical Science Monitor, vol. 13, no. 3, pp. MT1–MT5, 2007. View at: Google Scholar
  285. P. Kippelen, C. Caillaud, E. Robert, K. Masmoudi, and C. Préfaut, “Exhaled nitric oxide level during and after heavy exercise in athletes with exercise-induced hypoxaemia,” Pflügers Archiv, vol. 444, no. 3, pp. 397–404, 2002. View at: Publisher Site | Google Scholar
  286. M. J. Maroun, S. Mehta, R. Turcotte, M. G. Cosio, and S. N. Hussain, “Effects of physical conditioning on endogenous nitric oxide output during exercise,” Journal of Applied Physiology, vol. 79, no. 4, pp. 1219–1225, 1995. View at: Publisher Site | Google Scholar
  287. G. Sub-Committee, “Guidelines for the management of mild hypertension: memorandum from a World Health Organization/International Society of Hypertension meeting,” Journal of Hypertension, vol. 1993, no. 11, pp. 905–918, 1993. View at: Google Scholar
  288. A. V. Chobanian, “National heart, lung, and blood institute joint national committee on prevention, detection, evaluation, and treatment of high blood pressure; national high blood pressure education program coordinating committee: the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report,” JAMA, vol. 289, pp. 2560–2572, 2003. View at: Google Scholar
  289. K. Shimamoto, K. Ando, T. Fujita et al., “The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2014),” Hypertension Research, vol. 37, no. 4, pp. 253–390, 2014. View at: Google Scholar
  290. M. J. Gibala, J. P. Little, M. J. MacDonald, and J. A. Hawley, “Physiological adaptations to low-volume, high-intensity interval training in health and disease,” The Journal of Physiology, vol. 590, no. 5, pp. 1077–1084, 2012. View at: Publisher Site | Google Scholar
  291. C. A. Silva, F. S. L. Vasconcelos-Filho, M. Serafim et al., “Effect of high-intensity exercise on endothelial function in patients with T2dm,” Revista Brasileira de Medicina do Esporte, vol. 22, pp. 126–130, 2016. View at: Google Scholar
  292. G. Siasos, D. Athanasiou, G. Terzis et al., “Acute effects of different types of aerobic exercise on endothelial function and arterial stiffness,” European Journal of Preventive Cardiology, vol. 23, no. 14, pp. 1565–1572, 2016. View at: Publisher Site | Google Scholar
  293. C. McClean, R. A. Harris, M. Brown, J. C. Brown, and G. W. Davison, “Effects of exercise intensity on postexercise endothelial function and oxidative stress,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 723679, 8 pages, 2015. View at: Publisher Site | Google Scholar
  294. S. Battault, F. Singh, S. Gayrard, J. Zoll, C. Reboul, and G. Meyer, “Endothelial function does not improve with high-intensity continuous exercise training in SHR: implications of eNOS uncoupling,” Hypertension Research, vol. 39, no. 2, pp. 70–78, 2016. View at: Publisher Site | Google Scholar
  295. C. Goto, Y. Higashi, M. Kimura et al., “Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress,” Circulation, vol. 108, no. 5, pp. 530–535, 2003. View at: Publisher Site | Google Scholar
  296. A. Saborido, A. Naudí, M. Portero-Otín, R. Pamplona, and A. Megías, “Stanozolol treatment decreases the mitochondrial ROS generation and oxidative stress induced by acute exercise in rat skeletal muscle,” Journal of Applied Physiology, vol. 110, no. 3, pp. 661–669, 2011. View at: Publisher Site | Google Scholar
  297. K. M. Channon, “Tetrahydrobiopterin: a vascular redox target to improve endothelial function,” Current Vascular Pharmacology, vol. 10, no. 6, pp. 705–708, 2012. View at: Publisher Site | Google Scholar
  298. J. K. Bendall, N. J. Alp, N. Warrick et al., “Stoichiometric relationships between endothelial tetrahydrobiopterin, endothelial NO synthase (eNOS) activity, and eNOS coupling in vivo,” Circulation Research, vol. 97, no. 9, pp. 864–871, 2005. View at: Publisher Site | Google Scholar
  299. L. Plavsic, O. M. Knezevic, A. Sovtic et al., “Effects of high-intensity interval training and nutrition advice on cardiometabolic markers and aerobic fitness in adolescent girls with obesity,” Applied Physiology, Nutrition, and Metabolism, vol. 45, no. 3, pp. 294–300, 2020. View at: Publisher Site | Google Scholar
  300. K. A. Dias, C. B. Ingul, A. E. Tjønna et al., “Effect of high-intensity interval training on fitness, fat mass and cardiometabolic biomarkers in children with obesity: a randomised controlled trial,” Sports Medicine, vol. 48, no. 3, pp. 733–746, 2018. View at: Publisher Site | Google Scholar
  301. K. A. Dias, J. S. Coombes, D. J. Green et al., “Effects of exercise intensity and nutrition advice on myocardial function in obese children and adolescents: a multicentre randomised controlled trial study protocol,” BMJ Open, vol. 6, no. 4, article e010929, 2016. View at: Publisher Site | Google Scholar
  302. A. W. Midgley, L. R. McNaughton, and S. Carroll, “Physiological determinants of time to exhaustion during intermittent treadmill running at vV(.-)O (2max),” International Journal of Sports Medicine, vol. 28, no. 4, pp. 273–280, 2007. View at: Publisher Site | Google Scholar
  303. L. M. Ross, R. R. Porter, and J. L. Durstine, “High-intensity interval training (HIIT) for patients with chronic diseases,” Journal of Sport and Health Science, vol. 5, no. 2, pp. 139–144, 2016. View at: Publisher Site | Google Scholar
  304. V. L. Billat, J. Slawinski, V. Bocquet et al., “Intermittent runs at the velocity associated with maximal oxygen uptake enables subjects to remain at maximal oxygen uptake for a longer time than intense but submaximal runs,” European Journal of Applied Physiology, vol. 81, no. 3, pp. 188–196, 2000. View at: Publisher Site | Google Scholar
  305. K. L. Way, A. Sabag, R. N. Sultana et al., “The effect of low-volume high-intensity interval training on cardiovascular health outcomes in type 2 diabetes: A randomised controlled trial,” International Journal of Cardiology, vol. S0167-5273(20)33397-0, 2020. View at: Publisher Site | Google Scholar
  306. E. Ghasemi and S. Nayebifar, “Benefits of 10 weeks of high-intensity interval training and green tea supplementation on cardiovascular risk factors and VO2max in overweight women,” Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, vol. 24, p. 79, 2019. View at: Google Scholar
  307. L. Su, J. M. Fu, S. L. Sun et al., “Effects of HIIT and MICT on cardiovascular risk factors in adults with overweight and/or obesity: a meta-analysis,” PLoS One, vol. 14, no. 1, article e0210644, 2019. View at: Publisher Site | Google Scholar
  308. P. M. Tomko, R. J. Colquhoun, N. F. Banks et al., “A single resistance exercise session reduces high-fat meal-induced impairments in conduit artery function and microvascular reactivity,” The FASEB Journal, vol. 33, Supplement 1, pp. 699.3–699.3, 2019. View at: Google Scholar
  309. L. Bruyndonckx, V. Y. Hoymans, A. De Guchtenaere et al., “Diet, exercise, and endothelial function in obese adolescents,” Pediatrics, vol. 135, no. 3, pp. e653–e661, 2015. View at: Google Scholar
  310. N. M. Gilbertson, S. L. Miller, N. Z. M. Eichner, and S. K. Malin, “Endothelial function following interval exercise plus low-calorie diet treatment in obese females,” Physiological Reports, vol. 7, no. 18, article e14239, 2019. View at: Publisher Site | Google Scholar
  311. M. Shah, S. Bailey, A. Gloeckner et al., “Effect of acute exercise on postprandial endothelial function in postmenopausal women: a randomized cross-over study,” Journal of Investigative Medicine, vol. 67, no. 6, pp. 964–970, 2019. View at: Publisher Site | Google Scholar
  312. M. Ristow and S. Schmeisser, “Extending life span by increasing oxidative stress,” Free Radical Biology & Medicine, vol. 51, no. 2, pp. 327–336, 2011. View at: Publisher Site | Google Scholar

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