Table of Contents Author Guidelines Submit a Manuscript
Oxidative Medicine and Cellular Longevity
Volume 2015, Article ID 313021, 11 pages
http://dx.doi.org/10.1155/2015/313021
Review Article

The Protective Effect of Lipoic Acid on Selected Cardiovascular Diseases Caused by Age-Related Oxidative Stress

1Department of Applied Pharmacy, Department of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland
2Department of Cardiovascular Physiology, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland

Received 11 December 2014; Revised 16 March 2015; Accepted 25 March 2015

Academic Editor: Ersin Fadillioglu

Copyright © 2015 Beata Skibska and Anna Goraca. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Oxidative stress is considered to be the primary cause of many cardiovascular diseases, including endothelial dysfunction in atherosclerosis and ischemic heart disease, hypertension, and heart failure. Oxidative stress increases during the aging process, resulting in either increased reactive oxygen species (ROS) production or decreased antioxidant defense. The increase in the incidence of cardiovascular disease is directly related to age. Aging is also associated with oxidative stress, which in turn leads to accelerated cellular senescence and organ dysfunction. Antioxidants may help lower the incidence of some pathologies of cardiovascular diseases and have antiaging properties. Lipoic acid (LA) is a natural antioxidant which is believed to have a beneficial effect on oxidative stress parameters in relation to diseases of the cardiovascular system.

1. Introduction

Oxidative stress plays a key role in the development of many cardiovascular diseases, including atherosclerosis, hypertension, ischemia-reperfusion injury, and heart failure (Figure 1). There are many factors associated with oxidative stress, which lead to the development of these diseases. One of the main factors is overproduction of ROS, together with decreased nitric oxide bioavailability and reduced antioxidant capacity in the vasculature [1].

Figure 1: The adverse effect of age-related oxidative stress on some cardiovascular diseases: atherosclerosis, hypertension, ischemia-reperfusion, and heart failure.

Death due to cardiovascular diseases is the cause of mortality in 80% of people aged over 65 years. In addition, the aging process is associated with oxidative stress in the blood vessels and in the heart, which leads to the development of cardiovascular disease (CVD) [2].

According to the free radical theory of aging developed by Harman, the antioxidant defense mechanisms become less effective in people after the age of 40 [3, 4]. This results in fatty acid oxidation and lipid peroxidation, with consequent changes in the physical properties of cell membranes and phospholipids. As they have long half-lives and increased polarity, phospholipid peroxides are active intermediaries of the oxidation and reduction chain [5], which may migrate from point of origin to other places in the organism.

Excessive ROS production and weakened antioxidant mechanisms lead to the occurrence of oxidative stress and induction of apoptosis. ROS reacts with DNA, proteins, and lipids, resulting in the accumulation of products, the onset of degenerative processes, and, ultimately, the development of many serious diseases and aging. Although aging is a natural process, it is accelerated by ROS production.

Oxidative stress is an imbalance between production of ROS present in cells and the biological ability to detoxify the reactive intermediates or repair the harm caused [6]. Currently, antioxidants are used in order to reduce the production of ROS in cells and limit their harmful effects on the organism. One effective antioxidant is lipoic acid (LA).

LA is a natural antioxidant synthesized in the mitochondria of the liver and other tissues [7], which plays a crucial role in metabolism. Its antioxidant properties were first discovered in the 1950s [6] and later confirmed by subsequent studies [811]. Its strong reduction and low oxidation-reduction potential (−0.29 V) have made it the subject of many studies from various fields of medicine. It is currently regarded as one of the most potent cellular oxidation regulators [12]. LA is a remarkable compound that appears to slow the process of aging in animal experiments. Considering the strong antioxidant properties of lipoic acid, the purpose of this review is to present the protective role of LA on selected cardiovascular diseases.

2. Age-Related Oxidative Stress in Cardiovascular Diseases

2.1. Endothelial Dysfunction and Atherosclerosis

Endothelium of the blood vessels is involved in many physiological and pathological processes. It plays a very important role in the physiological regulation of vascular tone, vascular smooth muscle cell migration, cellular adhesion, and resistance to thrombosis [13].

Pathological processes which occur in blood vessels cause the endothelial balance to become dysregulated. This endothelial dysfunction contributes to the development of atherosclerosis, improper blood circulation, inflammation, and even cancer progression [14]. Vascular dysfunction is caused by reduction of nitric oxide levels, production of vasoconstrictor/vasodilator factor imbalances, impaired angiogenesis, endothelial cell senescence, and oxidative stress [15]. Although there are several conditions that contribute to endothelial dysfunction, increased oxidative stress seems to play an important role.

The overproduction of ROS is a result of the adverse effect of oxidative stress on cellular levels of nitric oxide (NO), an important endothelial factor. Recent studies suggest that NO is an important factor for the proper functioning of endothelial cells, because it controls the function of smooth muscle and exerts an antihypertensive effect at the cardiovascular level [16].

NO is synthesized from l-arginine by the enzyme NO synthase (NOS). There are three NOS isoforms: the neuronal isoforms (nNOS), the constitutive endothelial isoform (eNOS), and the inducible isoform (iNOS) [17]. The reduction of NO availability disturbs its vascular homeostasis.

Aging is a physiological process, but it also influences the destabilization of endothelial cells.

This process, and its associated increased oxidative stress, is one of the factors which may cause endothelial dysfunction. The consequence of increased oxidative stress in aging is inactivation of NO by high concentrations of produced by the reaction of NO with ROS [18, 19]. The reaction between NO and forms the peroxynitrite anion (ONOO). This form is known as a reactive nitrogen species (RNS) and characterized high reactivity with proteins, DNA, and lipids. Unlike , ONOO can penetrate into the cardiovascular cells and cause oxidative modifications within them [20]. Peroxynitrite has also been shown to induce microvascular hyperpermeability by disrupting the adherens junction proteins [21].

One in vitro study shows decreased eNOS expression in aged human umbilical vein endothelial cells. This process is associated with dysfunction of cell-cell junctions and microvascular hyperpermeability [22]. It leads to severe oxidative injury, which results in cell necrosis or apoptosis. This has been confirmed by many other studies which suggest that the decreased endothelial NO production promotes endothelial cell apoptosis and leads to microvascular rarefaction [23, 24].

Oxidative stress is known to activate redox-sensitive cellular signaling pathways, which have in turn been implicated in inflammation associated with vasculature subjected to aging [25]. According to in vitro studies on endothelial cells, this inflammation induces overproduction of ROS and endothelial dysfunction in older rats [26].

In recent years, longevity genes have been identified that affect lifespan and the rate at which the organism ages. For example, defects in mouse Klotho gene have been shown to be associated with endothelial dysfunction, leading to the premature development of atherosclerosis and, at the same time, accelerated aging [27].

Mouse models of mild dyslipidemia have been found to demonstrate endothelial dysfunction, for example, those which are deficient in apolipoprotein E. This endothelial dysfunction is associated with stretch-induced hypercontractility and diminished endothelium-dependent vasorelaxation, accompanied by decreased levels of NO and eNOS, as well as increased plasma levels of IL-6, a proinflammatory cytokine that reduces eNOS levels and activity. Endothelial dysfunction was found to precede the appearance of atherosclerosis in a murine model of dyslipidemia [28].

Atherosclerosis is a pathological state of the vasculature which progresses together with endothelial dysfunction caused by dyslipidemia, leading to the deposition of inflammatory cells and lipids in the vascular wall. Therefore, the state of the aging blood vessels, which are progressively damaged, primarily impacts the development of atherosclerosis. The oxidative stress theory of atherosclerosis indicates that the production of ROS stimulates oxidized low-density lipoprotein formation (ox-LDL) [29].

ox-LDL has many important properties which may promote atherosclerosis. It stimulates vascular ROS formation and causes endothelial dysfunction via NOX activation and endothelial (NO)-synthase (NOS) uncoupling [30]. In addition, Meisinger et al. note that it acts as a proatherogenic marker [31] and that elevated levels of ox-LDL may predict coronary heart disease events in healthy subjects. Moreover, ox-LDL is known to promote oxygen radical generation in human aortic endothelial cells (HEAC) by phosphorylating the p66Shc adaptor protein at Ser36 [14]. Hence, oxidation of LDL appears to contribute to the prooxidant environment in atherosclerotic lesions.

Current research shows that endothelial dysfunction also plays an important role in early and late mechanisms of atherosclerosis development.

Atherosclerosis is known to result in vascular events such as hypertension, ischemic heart failure, and heart failure.

2.2. Hypertension

Oxidative stress and aging are involved in hypertension. Both lead to overproduction of reactive oxygen species. The ROS generated in cardiovascular cells cause various forms of pathological vascular damage in blood vessels related to the promotion of cell growth, the accumulation of extracellular matrix protein, inflammation, and endothelial dysfunction, all of which are characteristic features of the hypertensive vascular phenotype [32].

As in atherosclerosis, one of the major mechanisms by which oxidative stress may promote hypertension is endothelial dysfunction. Aside from impaired vascular expansion, the most important effects of endothelial dysfunction are those concerned with two substances produced by the endothelium: NO and endothelin-1 (ET-1) [33]. An imbalance between these substances interferes with vascular homeostasis, leading to vasoconstriction and elevated blood pressure [34]. Disturbed homeostasis is characterized by an increase in the vasoconstriction factor ET-1 and a reduction of the bioavailability of NO [35]. Experimental evidence indicates that NO is inactivated by ROS, particularly and H2O2, leading to endothelial dysfunction and vasoconstriction [36]. Other studies have shown that ROS can be also generated in response to ET-1 [37].

ET-1 is a vasoconstrictor peptide, which raises blood pressure and induces vascular and myocardial hypertrophy [38]. ET-1 production is known to be influenced by a number of factors. Oxidative stress may cause modulation of ET-1 and in ET-1-induced activation of various signaling pathways [39]. In addition, aging may increase the release of ET-1 from endothelial cells in humans and animals [40, 41]. In turn, in vitro studies have shown that ET-1 itself activates many factors, including NFκB and TNF-α, which are involved in cell growth, inflammation, and proliferation [4244]. These processes can also affect the development of hypertension.

Along with NO deficiency and increased ET-1 production, a dysfunctional endothelium also acts as a source of other mediators and factors such as prostaglandin H2, tromboxane A2, ROS and angiotensin II (AT II) that damage vascular cells [45]. Both angiotensin II and endothelin-1 play important roles in age-related endothelial dysfunction [46]. Angiotensin II stimulates ET-1 release and raises blood pressure by a variety of actions [47] and is a potent activator of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase in vascular cells [48]. NAD(P)H is a major source of ROS in the blood vessels and is considered to be a critical determinant of the redox state of blood vessels [49]. Some studies suggest that enhanced NAD(P)H-oxidase activity can be observed in hypertension-induced oxidative stress and subsequently endothelial dysfunction. Another study confirms the role of NAD(P)H-oxidase on the formation of ROS in blood vessels. The activation of NAD(P)H-oxidase in cerebral blood vessels causes H2O2-mediated opening of BKCa channels in cerebral arteries, leading to consequent hyperpolarization and vasodilation [50]. In addition, oxidative stress activates other enzymes, including mitochondrial enzymes, NOS, and xanthine oxidase, which are produced following ROS production and have a damaging influence on blood vessels.

The relationship between oxidative stress and hypertension has been shown in many experimental models [5154]. Similarly, the renin-angiotensin aldosterone system (RAAS) is important in the pathogenesis of arterial ageing [55]. RAAS is one of the most important hormonal systems; it oversees the functions of the cardiovascular, renal, and adrenal glands by regulating blood pressure, fluid volume, and sodium and potassium balance. Disorders in RAAS function lead to endothelium dysfunction, which may be caused, inter alia, by age-related oxidative stress [56].

To summarize, hypertension may be triggered by a number of factors. However, oxidative stress and aging both exert a significant influence.

2.3. Atherosclerosis-Ischemic Heart Disease

Age-related oxidative stress also leads to cardiac ischemic and reperfusion injuries. Aging and oxidative stress play important roles in the senescent heart. The aged myocardium has less tolerance to ischemia and hemodynamic stress than the young myocardium [5759].

Many metabolic and biochemical changes in myocardial tissue are the result of oxygen and nutrient deprivation during ischemia. In most cases, the presence of atherosclerotic plaques slowly leads to the narrowing of blood vessels and impairs the blood supply to the heart. Long-term ischemic heart disease can lead to myocardial infarction due to myocardial hypoxia and accumulation of waste metabolites. This can lead to damage to the cardiovascular and cell death by apoptosis [60].

During reperfusion, the concentration of superoxide anions () and hydroxyl groups (OH) from mitochondria is greatly increased. Oxidative stress is then intensified by the increased production of these ROS, which then results in oxidation of mitochondrial proteins and mitochondrial dysfunction [61].

ROS such as superoxide anions, hydrogen peroxide, and hydroxyl groups can cause mitochondrial genomic damage and a gradual decline in mitochondrial function in senescent hearts [62]. Mitochondria from aged hearts have been found to demonstrate reduced membrane potential, which may contribute to lowered adenosine 5′-triphosphate (ATP) synthesis [63]. This imbalance between the synthesis and consumption of ATP significantly influences the metabolism of the heart muscle, leading to greater oxygen consumption. ATP deficiency is also associated with a rapid loss of myocardial contractility, which can result in dysfunctions of the cardiovascular system and arrhythmias [64].

ROS can also activate some biochemical pathways in blood vessels, resulting in changes in cell function. In response to angiotensin II induction, they can activate protein kinase B in vascular smooth muscle cells (VSMC), leading to VSMC hypertrophy [65]. The activation of biochemical signaling pathways promotes greater cellular dysfunction and impairs cardiomyocyte functionality [66].

Increased levels of inflammatory markers such as TNF-α, CRP, and IL-6 can be observed in ischemia-reperfusion damage. These compounds and other cytokines can increase the production of ROS in atherosclerosis by stimulating vascular myocytes. Conversely, by inducing inflammation, ROS may also further stimulate the production of inflammatory cytokines.

Furthermore, other biomarkers of oxidative stress play important roles in the pathophysiology of ischemia-reperfusion damage in myocardial infarction. Extracellular biomarkers of ischemia-reperfusion damage include lipid peroxidation products, plasma antioxidant vitamin levels, total antioxidant capacity of plasma, and protein carbonylation. In addition, such intracellular biomarkers as antioxidant enzyme activity, thiol index (GSH/GSSG ratio), carbonyl levels, and F2-isoprostane level can influence the degree of oxidative stress [67].

In general, an imbalance between the demand for oxygen and nutrients and the ability to deliver them to the heart muscle, known as ischemia-reperfusion, is most commonly caused by atherosclerosis, but oxidative stress and related overproduction of ROS also play important roles. They cause lipid, protein, and DNA oxidation, potentially contributing to contractile failure [68].

Ischemia can lead to various diseases of the heart such as heart failure and, ultimately, myocardial infarction, depending on the duration and extent of ischemia.

2.4. Heart Failure

The effects of oxidative stress on aging on the vasculature and on the heart muscle are varied but can lead to the development of heart failure (HF). Several cardiovascular diseases are connected with HF, for example, ischemic heart disease, atherosclerosis, hypertension, and cardiac hypertrophy. Oxidative stress and ROS accumulation contribute to all these and contribute to their progression.

In myocardial ischemia, hypoxia and reoxygenation elevate ROS production in cardiac tissues, which leads to direct oxidative damage to cellular components.

ROS influence the function of the extracellular matrix, which is demonstrated by greater interstitial and perivascular fibrosis [69].

On the cellular level, mitochondria are one of the major sites for the generation of ROS, which is an undesirable side product of the energy production. Therefore, mitochondrial dysfunction increases the risk of heart failure. Among the damage induced by ROS generated at the cellular level, mitochondrial DNA (mtDNA) remains the major target [70]. In experimental models, it has been proven that mtDNA deletions contribute to the phenotype of systolic heart failure through increased mtROS [58].

Oxidative stress changes gene expression and influences cell death in heart cells which are now known to exert an influence on heart failure and myocardial remodeling. Heart failure itself is known to involve a decrease in contractility, myocardial fibrosis, myocyte apoptosis, and metabolic remodeling [71]. Metabolic remodeling in heart failure is characterized by decreased cardiac energy production, which is the result of a decrease in the level of ATP in cardiomyocytes. This may lead to progressive impairments in substrate utilization and mitochondrial biogenesis and function. In addition to ATP deficiency, metabolic remodeling involves changes in metabolic pathways that regulate essential, non-ATP-generating cellular processes such as growth, redox homeostasis, and autophagy [72]. A reduced supply of ATP necessary for the contractile function of cardiomyocytes can account for chronic heart failure.

One cause of these processes is increased oxidative stress, which leads to the disruption of the structures of proteins, lipids, and nucleic acids. Several studies have demonstrated an association with these structural disorders and heart failure [73, 74].

In the failing heart, overproduction of ROS leads to the accumulation of superoxide anions, which may be generated by both metabolic and enzymatic sources, including nitric oxide synthase, NADPH oxidases, mitochondrial respiration, and xanthine oxidase [75].

Xanthine oxidase (XO) in particular exerts an important influence on heart failure. XO can also combine with other compounds and enzymes and create reactive oxidants, as well as oxide substrates. It has been found to be present in higher levels with greater activity in cases of heart failure. This upregulation can contribute to the energy disorder in myocardial cells [76].

Similarly, increased NAD(P)H activity has been observed in myocardial cells from humans with heart failure [77, 78]. This increase is due partly to the presence of increased concentrations of angiotensin II, which leads to an imbalance in the oxidative/nitrosative system [27]. In addition, ROS generated by NADPH oxidase proteins are also important in redox signaling [79].

In summary, multiple factors are involved in the etiology of heart failure, and oxidative stress is one of them. To reduce or prevent the adverse effects of oxidative stress on the organism, substances with antioxidant properties can be applied. Research indicates that dietary supplementation by exogenous antioxidants can play a key role in ameliorating many of the effects of oxidative stress in cardiovascular diseases.

3. Protective Effect of Lipoic Acid (LA) on Cardiovascular Diseases

Lipoic acid (LA) is a specific antioxidant; it can easily quench radicals, has an amphiphilic character, and does not exhibit any serious side effects [80]. LA a compound that contains sulfur in the form of two thiol groups [81] acts as a cofactor for several mitochondrial enzymes by catalyzing the α-ketoacid. The antioxidant properties of LA are based on its ability to directly scavenge ROS, its metal chelating activity, and its potential to react with, and regenerate, other antioxidants such as glutathione and vitamins E and C [82]. LA also demonstrates anti-inflammatory properties.

An additional advantage of LA is its solubility both in water and in fat, which allows it to travel to all parts of the body [83]. Because of its special properties, it is able to enter certain parts of the cell that most other antioxidants are not able to reach.

This compound acts by many mechanisms and can therefore be a very effective antioxidant. Hence, LA is used in various diseases concerning age-dependent oxidative stress. It can be particularly effective in cardiovascular diseases, including ischemic heart disease, hypertension, heart failure, and atherosclerosis, where it may slow aging and prolong lifespan.

3.1. Effect of Lipoic Acid in Atherosclerosis

Many studies have confirmed that LA can improve vascular function and decrease the atherosclerotic plaque burden [84, 85]. By chelating redox-active transition metal ions, LA is thought to inhibit the Fenton-like-reaction mechanism and inhibit the formation of OH. As a consequence, lipid peroxidation is inhibited in mitochondria [86].

A crucial regulator of vascular homeostasis is the renin-angiotensin-aldosterone system (RAAS). A key role in the pathogenesis of atherosclerosis is played by angiotensin II (Ang II). It induces oxidative stress and creates superoxide anions primarily through the activation of NAD(P)H-oxidase in vascular cells and myocytes. In addition, Ang II activates intracellular signaling pathways and upregulates many inflammation factors including chemokines, cytokines, and growth factors, which have been implicated in atherosclerotic plaque development.

LA reacts with ROS, such as superoxide anions, normalizes NADPH oxidase activity, and can prevent Ang II-induced macrophage, monocyte, and T cell infiltrations. It is also thought that LA can block AT1 receptors, which improves endothelial function and reduces plaque area in atherosclerosis [87].

Many clinical studies have shown that the beneficial effects of LA against Ang II are linked not only to scavenged ROS, but also to NF-kappaB inhibition. LA reduces NF-κB-mediated inflammatory responses by regulating the expression of proinflammatory genes and adhesion molecules [88]. It also reduces the chemokine and adhesion molecules involved in T cell trafficking to inhibition of monocyte-endothelial interactions by atherosclerotic plaque.

Many animal and human studies report that LA supplementation can result in reduced cholesterol levels [89, 90]. LA may also prevent LDL oxidation by reducing the concentrations of LDL-C, Ox-LDL, serum TC, and lipoprotein (a) [Lp(a)], as well as other oxidative biomarkers [85].

Clinical studies confirm that LA may also reduce the aortic expression of adhesion molecules and the accumulation of aortic macrophages and proinflammatory cytokines, resulting in reduced LDL level and triglyceride concentration and elevated HDL [91, 92]. In animal models, 12-week administration of LA reduced oxidative stress and improved vascular reactivity in animals fed with a high cholesterol diet [93]. LA may also be capable of initiating LDL receptor synthesis in the liver, resulting in increased return of cholesterol to the hepatic system and elevated synthesis of apoprotein A component (a HDL particle moiety) for reversed cholesterol transport [9496].

Finally, it can be concluded that LA has a direct lipid modulating action and an indirect effect on blood lipid levels, leading to reduced risk of atherosclerosis. It is used as a dietary supplement, either alone or with other oxidants; for example, vitamins C and E may represent a helpful strategy in reducing the adverse effects of oxidative stress.

3.2. Effect of Lipoic Acid in Hypertension

Hypertension increases the production of various inflammatory biomarkers. These include chemokines, such as monocyte chemoattractant protein 1 (MCP-1), adhesion molecules, such as P-selectin, and cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin- (IL-) 6. This elevated production of biomarkers results in reduced NO bioavailability, via NO degradation in vessel cells, and excessive production of endothelin I, which in turn impairs endothelium-dependent vasodilation [97]. ROS, particularly , bind NO and form highly reactive and dangerous ONOO. This ONOO produces a cascade of changes, which in turn lead to increased tension within the blood vessels.

Lipoic acid may have a beneficial effect in preventing the development of hypertension by lowering the level of inflammatory cytokines in the blood plasma, thus preventing these pathological changes to vessel cells and normalizing changes in blood pressure [98, 99]. Several clinical trials have shown that LA inhibits the vascular overproduction of endothelin I, the main vasoconstrictor [100]. Furthermore, LA significantly increases the synthesis of NO, the main vasodilator; it may also improve the redox state of the plasma and improve endothelium-dependent NO-mediated vasodilation. In addition, LA ameliorates the loss of eNOS phosphorylation, which contributes to improved endothelial function [101, 102]. It is also known to inhibit TNF-alpha activation [103]. As LA is a good metal chelator, it may also inhibit the production of adhesion molecules by monocytes, thus improving endothelial function. In one study, LA supplementation was found to reduce the aortic expression of adhesion molecules and proinflammatory factors, such as lowering the accumulation of aortic macrophages [96].

Furthermore, LA could potentially regulate intracellular Ca2+ levels by preventing the modification of sulfhydryl groups in the Ca2+ channels [104]. Another study shows that LA increases tissue GSH levels, which otherwise decline with age, by restoring glutathione peroxidase activity [105, 106].

The antioxidant properties of LA cause it to exert a “rejuvenative” impact on mitochondria by protecting them against the higher levels of ROS they produce during the aging process. LA increases oxygen consumption and mitochondrial membrane potential, while decreasing the mitochondrial production of oxidants by amplifying the activity of antioxidant mechanisms [107]. However, despite LA supplementation not being particularly effective in this regard, it can nevertheless significantly reduce blood pressure when used in combination with other antioxidants such as L-carnitine [108].

3.3. Effect of Lipoic Acid in Atherosclerosis-Ischemic Heart Disease

Ischemia injury can follow oxidative stress and can lead to significant morbidity and mortality. During ischemia, specific changes in the antioxidant system can occur, resulting in injury to organs such as the kidney, liver, or heart.

In ischemia, oxidative stress causes many complication reactions involving adhesion molecules and cytokines, leading to massive release of ROS. This process increases the production of tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) through activation of NF-κB. Furthermore, increases in intracellular Ca2+ concentration and MDA levels result in decreases in GPx and SOD reactivity [109], thus inducing contractile dysfunction, hypertrophy, fibrosis, and cell death [110]. Contractile function and arrhythmias may also be depressed [111]. Clinical studies indicate that up to 50% of the final infarct may be attributable to ischemia injury in both animals and humans [67].

LA counteracts the damage associated with the ischemia experimental model. It can provide protection against ischemia by inhibiting ROS production, blocking inflammation, and reducing myocardium apoptosis, as noted above. Recent studies indicate that LA prevents postreperfusion arrhythmias and protects cardiomyocytes from hypoxia-induced death [112]. It induces cardioprotection through a number of routes: inhibition of NOX4 activity leading to NOS recoupling, improved NO bioavailability, and reduced oxidative stress, leading ultimately to the preservation of mitochondrial function. In addition, LA limits further damage caused by ischemia by increasing Akt phosphorylation via the activation of the PI3K/Akt pathway and the induction of cytoprotective genes [113]. It also prevents decreases in ATP content and the activation of proinflammatory factor NF-κB. In animal models of ischemia, LA was found to ameliorate cardiac dysfunction with reduced infarct size and lower levels of myeloperoxidase, TNF-α, creatinine kinase, and lactate dehydrogenase, while upregulating the expression of several antioxidant enzyme genes [114]. Other studies report that LA administration bestows significant protective effects by raising MDA levels and lowering the activity of glutathione peroxidase (GPx) and superoxide dismutase (SOD), the enzymatic scavengers of ROS [109].

Another way to protect the cardiovascular system from oxidative stress is based on its capacity to regenerate endogenous antioxidants such as vitamins C and E. It also regenerates glutathione, which plays a very important role in maintaining the balance between antioxidants and prooxidants. LA may increase the levels of glutathione and other natural antioxidants, thus preventing the progression of ischemia [115].

3.4. Effect of Lipoic Acid in Heart Failure

Heart failure (HF) may cause severe damage to the heart muscle via myocardial fibrosis, ventricular remodeling, decreased contractility, and increased myocyte apoptosis [14]. Mitochondrial damage is central to the pathophysiology of HF. The mechanism of mitochondrial dysfunction is connected with cellular and mitochondrial damage which impairs the mechanical properties of the heart. In age-related oxidative stress, a reduced supply of energy from the mitochondria necessary for the contractile function of cardiomyocytes is often noted [116]. Therefore, one strategy in treating HF is the stimulation of cardiac systolic function by targeting mitochondrial dysfunction.

Cardiomyocyte function is disturbed in HF, but not irreversibly [117]. The cardiomyocytes respond to oxidative stress by increasing antioxidant system activity: increased thioredoxin system (Trx) activity has been observed, together with greater mRNA expression of several antioxidant enzymes [118]. Myocardial energy efficiency can be improved by up to 30% by using strategies based on increasing glucose oxidation and decreasing fatty acid metabolism [117].

Many studies on animal models have confirmed that LA can prevent progressive remodeling and even improve cardiac function [119]. By acting as a cofactor for enzymatic reactions within the mitochondria, it can improve mitochondrial function by conserving cellular energy [120]. Thus, LA can influence mitochondrial antioxidant status, neutralize ROS, and effectively attenuate mitochondrial damage caused by oxidative stress and the aging process [121]. Antioxidants such as LA are widely regarded as attractive novel agents which can be employed to prevent oxidative stress when targeted at the mitochondria [122]. Several studies have demonstrated that LA administration effectively attenuates cardiac apoptosis [123, 124]. It has been found to attenuate oxidative damage to the mitochondria, with increased GSH levels and enhanced SOD activity being observed [123]. It has also been seen to mediate the elevation of cellular defense, which may be associated with greater resistance to ROS-elicited cardiac cell injury [124]. Finally, it has also been demonstrated that LA reinforces cellular defenses by inducing endogenous antioxidants and phase 2 enzymes in cultured cardiac cells. These have been associated with markedly increased resistance to ROS-elicited cardiomyocyte injury [124].

All the above examples indicate that LA may be helpful in treating HF caused by oxidative stress. It offers a number of benefits concerned with preventing oxidative damage to the mitochondria, on both molecular and genetic levels, even when applied at low concentrations. Its use in this regard merits further study.

4. Summary

In the last years, investigations in human and animal models have provided abundant evidence that age-dependent oxidative stress plays an important role in cardiovascular diseases. Studies indicate that antioxidants prevent development of many cardiovascular diseases and may even improve course of diseases, such as atherosclerosis, hypertension, ischemia-reperfusion, or heart failure. It is therefore disappointing that very few applications have been found for antioxidants in these diseases.

Lipoic acid can provide protection against ROS-induced damage under conditions of elevated oxidative stress brought on by the aging organism. It meets all the criteria for an ideal antioxidant, because it may reduce adverse effects of oxidative stress, has amphiphilic properties, and does not exhibit any serious side effects [125].

However, the results of clinical trials intake of exogenous antioxidant are contradictory. No beneficial effects were reported in several studies in which only one synthetic antioxidant was used. Therefore, a better antioxidant effect can be achieved using more than one antioxidant.

Abbreviations

ROS:Reactive oxygen species
LA:Lipoic acid
NO:Nitric oxide
RNS:Reactive nitrogen species
NOS:Nitric oxide synthase
CVD:Cardiovascular disease
ox-LDL:Oxidized low-density lipoprotein
TNF-α:Tumor necrosis factor-alpha
ET-1:Endothelin-1
AT II:Angiotensin II
NAD(P)H:Nicotinamide adenine dinucleotide phosphate
RAAS:Renin-angiotensin aldosterone system
ATP:Adenosine 5′-triphosphate
HF:Heart failure
mtDNA:Mitochondrial DNA
GSH:Reduced glutathione
SOD:Superoxide dismutase.

Conflict of Interests

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

Acknowledgment

The study was supported by Grant no. 503/0-079-03/503-01 from the Medical University of Lodz.

References

  1. T. M. Paravicini and R. M. Touyz, “NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities,” Diabetes care, vol. 31, no. 2, pp. 170–180, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. A. Karavidas, G. Lazaros, D. Tsiachris, and V. Pyrgakis, “Aging and the cardiovascular system,” Hellenic Journal of Cardiology, vol. 51, no. 5, pp. 421–427, 2010. View at Google Scholar · View at Scopus
  3. Y. Mei, M. D. Thompson, R. A. Cohen, and X. Tong, “Autophagy and oxidative stress in cardiovascular diseases,” Biochimica et Biophysica Acta, vol. 1852, no. 2, pp. 243–251, 2015. View at Publisher · View at Google Scholar
  4. D. Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of Gerontology, vol. 11, no. 3, pp. 298–300, 1956. View at Publisher · View at Google Scholar · View at Scopus
  5. G. Bartosz, “Reactive oxygen species: destroyers or messengers?” Biochemical Pharmacology, vol. 77, no. 8, pp. 1303–1315, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. L. J. Reed, “The chemistry and function of lipoic acid,” Advances in Enzymology and Related Subjects of Biochemistry, vol. 18, pp. 319–347, 1957. View at Google Scholar · View at Scopus
  7. M. Dudek, A. Bilska-Wilkosz, J. Knutelska et al., “Are anti-inflammatory properties of lipoic acid associated with the formation of hydrogen sulfide?” Pharmacological Reports, vol. 65, no. 4, pp. 1018–1024, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. L. Packer, E. H. Witt, and H. J. Tritschler, “Alpha-lipoic acid as a biological antioxidant,” Free Radical Biology and Medicine, vol. 19, no. 2, pp. 227–250, 1995. View at Publisher · View at Google Scholar · View at Scopus
  9. F. Navari-Izzo, M. F. Quartacci, and C. Sgherri, “Lipoic acid: a unique antioxidant in the detoxification of activated oxygen species,” Plant Physiology and Biochemistry, vol. 40, no. 6–8, pp. 463–470, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Ghibu, C. Richard, C. Vergely, M. Zeller, Y. Cottin, and L. Rochette, “Antioxidant properties of an endogenous thiol: alpha-lipoic acid, useful in the prevention of cardiovascular diseases,” Journal of Cardiovascular Pharmacology, vol. 54, no. 5, pp. 391–398, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. L. Rochette, S. Ghibu, C. Richard, M. Zeller, Y. Cottin, and C. Vergely, “Direct and indirect antioxidant properties of α-lipoic acid and therapeutic potential,” Molecular Nutrition and Food Research, vol. 57, no. 1, pp. 114–125, 2013. View at Publisher · View at Google Scholar · View at Scopus
  12. A. Bilska and L. Włodek, “Lipoic acid—the drug of the future?” Pharmacological Reports, vol. 57, no. 5, pp. 570–577, 2005. View at Google Scholar · View at Scopus
  13. C. Steyers and F. Miller, “Endothelial dysfunction in chronic inflammatory diseases,” International Journal of Molecular Sciences, vol. 15, no. 7, pp. 11324–11349, 2014. View at Publisher · View at Google Scholar
  14. N. R. Madamanchi and M. S. Runge, “Redox signaling in cardiovascular health and disease,” Free Radical Biology and Medicine, vol. 61, pp. 473–501, 2013. View at Publisher · View at Google Scholar · View at Scopus
  15. M. E. Rubio-Ruiz, I. Pérez-Torres, M. E. Soto, G. Pastelín, and V. Guarner-Lans, “Aging in blood vessels. Medicinal agents FOR systemic arterial hypertension in the elderly,” Ageing Research Reviews, vol. 18, pp. 132–147, 2014. View at Publisher · View at Google Scholar
  16. M. Monti, R. Solito, L. Puccetti et al., “Protective effects of novel metal-nonoates on the cellular components of the vascular system,” Journal of Pharmacology and Experimental Therapeutics, vol. 351, no. 3, pp. 500–509, 2014. View at Publisher · View at Google Scholar
  17. M. El Assar, J. Angulo, S. Vallejo, C. Peiró, C. F. Sánchez-Ferrer, and L. Rodríguez-Mañas, “Mechanisms involved in the aging-induced vascular dysfunction,” Frontiers in Physiology, vol. 3, article 132, Article ID Article 132, pp. 1–13, 2012. View at Publisher · View at Google Scholar · View at Scopus
  18. R. Oakley and B. Tharakan, “Vascular hyperpermeability and aging,” Aging and Disease, vol. 5, no. 2, pp. 114–125, 2014. View at Publisher · View at Google Scholar
  19. 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 · View at Google Scholar · View at Scopus
  20. P. Pacher, J. S. Beckman, and L. Liaudet, “Nitric oxide and peroxynitrite in health and disease,” Physiological Reviews, vol. 87, no. 1, pp. 315–424, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. Y. Zhang, S. Zhao, Y. Gu, D. F. Lewis, J. S. Alexander, and Y. Wang, “Effects of peroxynitrite and superoxide radicals on endothelial monolayer permeability: potential role of peroxynitrite in preeclampsia,” Journal of the Society for Gynecologic Investigation, vol. 12, no. 8, pp. 586–592, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. H. J. Yoon, S. W. Cho, B. W. Ahn, and S. Y. Yang, “Alterations in the activity and expression of endothelial NO synthase in aged human endothelial cells,” Mechanisms of Ageing and Development, vol. 131, no. 2, pp. 119–123, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. A. Csiszar, Z. Ungvari, A. Koller, J. G. Edwards, and G. Kaley, “Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging,” Physiological Genomics, vol. 17, pp. 21–30, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Csiszar, N. Labinskyy, Z. Orosz, Z. Xiangmin, R. Buffenstein, and Z. Ungvari, “Vascular aging in the longest-living rodent, the naked mole rat,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 293, no. 2, pp. H919–H927, 2007. View at Publisher · View at Google Scholar · View at Scopus
  25. A. Csiszar, M. Wang, E. G. Lakatta, and Z. Ungvari, “Inflammation and endothelial dysfunction during aging: role of NF-kappaB,” Journal of Applied Physiology, vol. 105, no. 4, pp. 1333–1341, 2008. View at Publisher · View at Google Scholar · View at Scopus
  26. H. Cai and D. G. Harrison, “Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress,” Circulation Research, vol. 87, no. 10, pp. 840–844, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. Y. Saito, M. Kurabayashi, T. Nakamura, and R. Nagai, “Klotho gene and endothelial function,” Nihon Ronen Igakkai Zasshi, vol. 43, no. 3, pp. 342–344, 2006. View at Publisher · View at Google Scholar · View at Scopus
  28. V. Cavieres, K. Valdes, B. Moreno, R. Moore-Carrasco, and D. R. Gonzalez, “Vascular hypercontractility and endothelial dysfunction before development of atherosclerosis in moderate dyslipidemia: role for nitric oxide and interleukin-6,” American Journal of Cardiovascular Disease, vol. 4, no. 3, pp. 114–122, 2014. View at Google Scholar
  29. G. M. Chisolm and D. Steinberg, “The oxidative modification hypothesis of atherogenesis: an overview,” Free Radical Biology and Medicine, vol. 28, no. 12, pp. 1815–1826, 2000. View at Publisher · View at Google Scholar · View at Scopus
  30. H. Mangge, K. Becker, D. Fuchs, and J. M. Gostner, “Antioxidants, inflammation and cardiovascular disease,” World Journal of Cardiology, vol. 6, no. 6, pp. 462–477, 2014. View at Publisher · View at Google Scholar
  31. C. Meisinger, J. Baumert, N. Khuseyinova, H. Loewel, and W. Koenig, “Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population,” Circulation, vol. 112, no. 5, pp. 651–657, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. A. H. Sprague and R. A. Khalil, “Inflammatory cytokines in vascular dysfunction and vascular disease,” Biochemical Pharmacology, vol. 78, no. 6, pp. 539–552, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. A. R. Weseler and A. Bast, “Oxidative stress and vascular function: implications for pharmacologic treatments,” Current Hypertension Reports, vol. 12, no. 3, pp. 154–161, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. T. Watson, P. K. Y. Goon, and G. Y. H. Lip, “Endothelial progenitor cells, endothelial dysfunction, inflammation, and oxidative stress in hypertension,” Antioxidants and Redox Signaling, vol. 10, no. 6, pp. 1079–1088, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. M. D. Herrera, C. Mingorance, R. Rodríguez-Rodríguez, and M. Alvarez de Sotomayor, “Endothelial dysfunction and aging: an update,” Ageing Research Reviews, vol. 9, no. 2, pp. 142–152, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Kajiya, M. Hirota, Y. Inai et al., “Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 292, no. 6, pp. H2737–H2744, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. A. Piechota, A. Polańczyk, and A. Goraca, “Role of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress,” Pharmacological Reports, vol. 62, no. 1, pp. 28–34, 2010. View at Google Scholar · View at Scopus
  38. D. Versari, E. Daghini, A. Virdis, L. Ghiadoni, and S. Taddei, “Endothelium-dependent contractions and endothelial dysfunction in human hypertension,” British Journal of Pharmacology, vol. 157, no. 4, pp. 527–536, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Kowalczyk, P. Kleniewska, M. Kolodziejczyk, B. Skibska, and A. Goraca, “The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis,” Archivum Immunologiae et Therapiae Experimentalis, vol. 63, no. 1, pp. 41–52, 2015. View at Publisher · View at Google Scholar
  40. T. Kumazaki, “Modulation of gene expression during aging of human vascular endothelial cells,” Hiroshima Journal of Medical Sciences, vol. 42, no. 2, pp. 97–100, 1993. View at Google Scholar · View at Scopus
  41. R. P. Brandes, I. Fleming, and R. Busse, “Endothelial aging,” Cardiovascular Research, vol. 66, no. 2, pp. 286–294, 2005. View at Publisher · View at Google Scholar · View at Scopus
  42. T. G. Canty Jr., E. M. Boyle Jr., A. Farr, E. N. Morgan, E. D. Verrier, and T. H. Pohlman, “Oxidative stress induces NF-κB nuclear translocation without degradation of IκBα,” Circulation, vol. 100, no. 19, pp. 361–364, 1999. View at Publisher · View at Google Scholar · View at Scopus
  43. P. Kleniewska, A. Piechota-Polanczyk, L. Michalski et al., “Influence of block of NF-kappa B signaling pathway on oxidative stress in the liver homogenates,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 308358, 8 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  44. S. R. Bhatt, M. F. Lokhandwala, and A. A. Banday, “Vascular oxidative stress upregulates angiotensin II type I receptors via mechanisms involving nuclear factor kappa B,” Clinical and Experimental Hypertension, vol. 36, no. 6, pp. 367–373, 2014. View at Publisher · View at Google Scholar
  45. 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, no. 2, pp. 314–321, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. O. Yildiz, “Vascular smooth muscle and endothelial functions in aging,” Annals of the New York Academy of Sciences, vol. 1100, pp. 353–360, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. D. E. Kohan, E. W. Inscho, D. Wesson, and D. M. Pollock, “Physiology of endothelin and the kidney,” Comprehensive Physiology, vol. 1, no. 2, pp. 883–919, 2011. View at Publisher · View at Google Scholar · View at Scopus
  48. G. R. Drummond, S. Selemidis, K. K. Griendling, and C. G. Sobey, “Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets,” Nature Reviews Drug Discovery, vol. 10, no. 6, pp. 453–471, 2011. View at Publisher · View at Google Scholar · View at Scopus
  49. P. N. Seshiah, D. S. Weber, P. Rocic, L. Valppu, Y. Taniyama, and K. K. Griendling, “Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators,” Circulation Research, vol. 91, no. 5, pp. 406–413, 2002. View at Publisher · View at Google Scholar · View at Scopus
  50. T. M. Paravicini, S. Chrissobolis, G. R. Drummond, and C. G. Sobey, “Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo,” Stroke, vol. 35, no. 2, pp. 584–589, 2004. View at Publisher · View at Google Scholar · View at Scopus
  51. R. M. Touyz, “Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension. What is the clinical significance?” Hypertension, vol. 44, no. 3, pp. 248–252, 2004. View at Publisher · View at Google Scholar · View at Scopus
  52. Q. N. Dinh, G. R. Drummond, C. G. Sobey, and S. Chrissobolis, “Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension,” BioMed Research International, vol. 2014, pp. 1–11, 2014. View at Publisher · View at Google Scholar
  53. M. M. Govender and A. Nadar, “A subpressor dose of angiotensin II elevates blood pressure in a normotensive rat model by oxidative stress,” Physiological Research. In press.
  54. M. P. Ocaranza, J. Moya, V. Barrientos et al., “Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis,” Journal of Hypertension, vol. 32, no. 4, pp. 771–783, 2014. View at Publisher · View at Google Scholar · View at Scopus
  55. S.-J. Lee and S.-H. Park, “Arterial ageing,” Korean Circulation Journal, vol. 43, no. 2, pp. 73–79, 2013. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Pacurari, R. Kafoury, P. B. Tchounwou, and K. Ndebele, “The renin-angiotensin-aldosterone system in vascular inflammation and remodeling,” International Journal of Inflammation, vol. 2014, Article ID 689360, 13 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  57. D. F. Dai, Y. A. Chiao, D. J. Marcinek, H. H. Szeto, and P. S. Rabinovitch, “Mitochondrial oxidative stress in aging and healthspan,” Longevity & Healthspan, vol. 3, article 6, 2014. View at Publisher · View at Google Scholar
  58. E. J. Lesnefsky, S. Moghaddas, B. Tandler, J. Kerner, and C. L. Hoppel, “Mitochondrial dysfunction in cardiac disease: ischemia—reperfusion, aging, and heart failure,” Journal of Molecular and Cellular Cardiology, vol. 33, no. 6, pp. 1065–1089, 2001. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Pepe, “Mitochondrial function in ischaemia and reperfusion of the ageing heart,” Clinical and Experimental Pharmacology and Physiology, vol. 27, no. 9, pp. 745–750, 2000. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Khurana, K. Venkataraman, A. Hollingsworth, M. Piche, and T. C. Tai, “Polyphenols: benefits to the cardiovascular system in health and in aging,” Nutrients, vol. 5, no. 10, pp. 3779–3827, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. T. Yamamoto and J. Sadoshima, “Protection of the heart against ischemia/reperfusion by silent information regulator 1,” Trends in Cardiovascular Medicine, vol. 21, no. 1, pp. 27–32, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Jahangir, S. Sagar, and A. Terzic, “Aging and cardioprotection,” Journal of Applied Physiology, vol. 103, no. 6, pp. 2120–2128, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. F. Di Lisa and P. Bernardi, “Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition,” Cardiovascular Research, vol. 66, no. 2, pp. 222–232, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Avkiran and M. S. Marber, “Na+/H+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects,” Journal of the American College of Cardiology, vol. 39, no. 5, pp. 747–753, 2002. View at Publisher · View at Google Scholar · View at Scopus
  65. N. Gonzaga, G. E. Callera, A. Yogi et al., “Acute ethanol intake induces mitogen-activated protein kinase activation, platelet-derived growth factor receptor phosphorylation, and oxidative stress in resistance arteries,” Journal of Physiology and Biochemistry, vol. 70, no. 2, pp. 509–523, 2014. View at Publisher · View at Google Scholar · View at Scopus
  66. T. Finkel and N. J. Holbrook, “Oxidants, oxidative stress and the biology of ageing,” Nature, vol. 408, no. 6809, pp. 239–247, 2000. View at Publisher · View at Google Scholar · View at Scopus
  67. R. Rodrigo, M. Libuy, F. Feliú, and D. Hasson, “Oxidative stress-related biomarkers in essential hypertension and ischemia-reperfusion myocardial damage,” Disease Markers, vol. 35, no. 6, pp. 773–790, 2013. View at Publisher · View at Google Scholar · View at Scopus
  68. P. Ferdinandy, R. Schulz, and G. F. Baxter, “Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning,” Pharmacological Reviews, vol. 59, no. 4, pp. 418–458, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. S. K. Maulik and S. Kumar, “Oxidative stress and cardiac hypertrophy: a review,” Toxicology Mechanisms and Methods, vol. 22, no. 5, pp. 359–366, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. T. A. Ajith, “Mitochondria-targeted agents: fture perspectives of mitochondrial pharmaceutics in cardiovascular diseases,” World Journal of Cardiology, vol. 6, no. 10, pp. 1091–1099, 2014. View at Publisher · View at Google Scholar
  71. S. Zhou, W. Sun, Z. Zhang, and Y. Zheng, “The role of Nrf2-mediated pathway in cardiac remodeling and heart failure,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 260429, 16 pages, 2014. View at Publisher · View at Google Scholar
  72. T. Doenst, T. D. Nguyen, and E. D. Abel, “Cardiac metabolism in heart failure: implications beyond atp production,” Circulation Research, vol. 113, no. 6, pp. 709–724, 2013. View at Publisher · View at Google Scholar · View at Scopus
  73. V. A. Cameron, T. J. Mocatta, A. P. Pilbrow et al., “Angiotensin type-1 receptor A1166C gene polymorphism correlates with oxidative stress levels in human heart failure,” Hypertension, vol. 47, no. 6, pp. 1155–1161, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Wojciechowska, E. Romuk, A. Tomasik et al., “Oxidative stress markers and C-reactive protein are related to severity of heart failure in patients with dilated cardiomyopathy,” Mediators of Inflammation, vol. 2014, Article ID 147040, 10 pages, 2014. View at Publisher · View at Google Scholar
  75. B. Douglas and M. D. Sawyer, “Oxidative stress in heart failure: what are we missing?” American Journal of the Medical Sciences, vol. 342, no. 2, pp. 120–124, 2011. View at Publisher · View at Google Scholar · View at Scopus
  76. M. M. Elahi, Y. X. Kong, and B. M. Matata, “Oxidative stress as a mediator of cardiovascular disease,” Oxidative Medicine and Cellular Longevity, vol. 2, no. 5, pp. 259–269, 2009. View at Publisher · View at Google Scholar · View at Scopus
  77. K. Venkataraman, S. Khurana, and T. C. Tai, “Oxidative stress in aging-matters of the heart and mind,” International Journal of Molecular Sciences, vol. 14, no. 9, pp. 17897–17925, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. J. Peng, B. Liu, Q. L. Ma, and X. J. Luo, “Dysfunctional endothelial progenitor cells in cardiovascular diseases: role of NADPH oxidase,” Journal of Cardiovascular Pharmacology, vol. 65, no. 1, pp. 80–87, 2015. View at Publisher · View at Google Scholar
  79. A. D. Hafstad, A. A. Nabeebaccus, and A. M. Shah, “Novel aspects of ROS signalling in heart failure,” Basic Research in Cardiology, vol. 108, no. 4, article 359, 2013. View at Publisher · View at Google Scholar · View at Scopus
  80. A. Gora̧ca, H. Huk-Kolega, A. Piechota, P. Kleniewska, E. Ciejka, and B. Skibska, “Lipoic acid—biological activity and therapeutic potential,” Pharmacological Reports, vol. 63, no. 4, pp. 849–858, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. G. K. Glantzounis, W. Yang, R. S. Koti, D. P. Mikhailidis, A. M. Seifalian, and B. R. Davidson, “The role of thiols in liver ischemia-reperfusion injury,” Current Pharmaceutical Design, vol. 12, no. 23, pp. 2891–2901, 2006. View at Publisher · View at Google Scholar · View at Scopus
  82. U. Singh and I. Jialal, “Alpha-lipoic acid supplementation and diabetes,” Nutrition Reviews, vol. 66, no. 11, pp. 646–657, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. A. Segall, M. Sosa, A. Alami et al., “Stability study of lipoic acid in the presence of vitamins A and E in o/w emulsions for cosmetic application,” Journal of Cosmetic Science, vol. 55, no. 5, pp. 449–461, 2004. View at Google Scholar · View at Scopus
  84. S. D. Wollin and P. J. H. Jones, “Alpha-lipoic acid and cardiovascular disease,” Journal of Nutrition, vol. 133, no. 11, pp. 3327–3330, 2003. View at Google Scholar · View at Scopus
  85. A. L. Catapano, F. M. Maggi, and E. Tragni, “Low density lipoprotein oxidation, antioxidants, and atherosclerosis,” Current Opinion in Cardiology, vol. 15, no. 5, pp. 355–363, 2000. View at Publisher · View at Google Scholar · View at Scopus
  86. I. Sadowska-Bartosz and G. Bartosz, “Effect of antioxidants supplementation on aging and longevity,” BioMed Research International, vol. 2014, Article ID 404680, 17 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Sola, M. Q. S. Mir, F. A. Cheema et al., “Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study,” Circulation, vol. 111, no. 3, pp. 343–348, 2005. View at Publisher · View at Google Scholar · View at Scopus
  88. L. Packer, K. Kraemer, and G. Rimbach, “Molecular aspects of lipoic acid in the prevention of diabetes complications,” Nutrition, vol. 17, no. 10, pp. 888–895, 2001. View at Publisher · View at Google Scholar · View at Scopus
  89. T. C. Rideout, B. Carrier, S. Wen, A. Raslawsky, R. W. Browne, and S. V. Harding, “Complementary cholesterol-lowering response of a phytosterol/alpha-Lipoic acid combination in obese zucker rats,” Journal of Dietary Supplements, 2015. View at Publisher · View at Google Scholar
  90. D. C. Kim, D. W. Jun, E. C. Jang et al., “Lipoic acid prevents the changes of intracellular lipid partitioning by free fatty acid,” Gut and Liver, vol. 7, no. 2, pp. 221–227, 2013. View at Publisher · View at Google Scholar · View at Scopus
  91. B. Carrier, S. Wen, S. Zigouras et al., “Alpha-lipoic acid reduces LDL-particle number and PCSK9 concentrations in high-fat fed obese zucker rats,” PLoS ONE, vol. 9, no. 3, Article ID e90863, 2014. View at Publisher · View at Google Scholar · View at Scopus
  92. Y. Zhang, P. Han, N. Wu et al., “Amelioration of lipid abnormalities by α-lipoic acid through antioxidative and anti-inflammatory effects,” Obesity, vol. 19, no. 8, pp. 1647–1653, 2011. View at Publisher · View at Google Scholar · View at Scopus
  93. Z. Ying, N. Kherada, B. Farrar et al., “Lipoic acid effects on established atherosclerosis,” Life Sciences, vol. 86, no. 3-4, pp. 95–102, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. S. V. Harding, T. C. Rideout, and P. J. H. Jones, “Evidence for using alpha-lipoic acid in reducing lipoprotein and inflammatory related atherosclerotic risk,” Journal of Dietary Supplements, vol. 9, no. 2, pp. 116–127, 2012. View at Publisher · View at Google Scholar · View at Scopus
  95. W.-J. Zhang, K. E. Bird, T. S. McMillen, R. C. LeBoeuf, T. M. Hagen, and B. Frei, “Dietary α-lipoic acid supplementation inhibits atherosclerotic lesion development in apolipoprotein E-deficient and apolipoprotein E/low-density lipoprotein receptor-deficient mice,” Circulation, vol. 117, no. 3, pp. 421–428, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. Z. Amom, Z. Zakaria, J. Mohamed et al., “Lipid lowering effect of antioxidant alpha-lipoic acid in experimental atherosclerosis,” Journal of Clinical Biochemistry and Nutrition, vol. 43, no. 2, pp. 88–94, 2008. View at Publisher · View at Google Scholar · View at Scopus
  97. S. Vasdev, J. Stuckless, and V. Richardson, “Role of the immune system in hypertension: modulation by dietary antioxidants,” International Journal of Angiology, vol. 20, no. 4, pp. 189–212, 2011. View at Publisher · View at Google Scholar · View at Scopus
  98. J. Leong, S. Pepe, J. Van der Merwe et al., “Preoperative metabolic therapy improves cardiac surgical outcomes: a prospective randomized clinical trial,” Heart, Lung and Circulation, vol. 16, supplement 2, p. S178, 2007. View at Publisher · View at Google Scholar
  99. S. R. Lee, M. H. Jeong, S. Y. Lim et al., “The effect of alpha lipoic acid (Thioctacid HR) on endothelial function in diabetic and hypertensive patients,” Korean Circulation Journal, vol. 36, no. 8, pp. 559–564, 2006. View at Publisher · View at Google Scholar · View at Scopus
  100. M. Takaoka, Y. Kobayashi, M. Yuba, M. Ohkita, and Y. Matsumura, “Effects of α-lipoic acid on deoxycorticosterone acetate-salt-induced hypertension in rats,” European Journal of Pharmacology, vol. 424, no. 2, pp. 121–129, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. T. Heitzer, B. Finckh, S. Albers, K. Krohn, A. Kohlschütter, and T. Meinertz, “Beneficial effects of α-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress,” Free Radical Biology and Medicine, vol. 31, no. 1, pp. 53–61, 2001. View at Publisher · View at Google Scholar · View at Scopus
  102. C. M. Sena, E. Nunes, T. Louro et al., “Effects of α-lipoic acid on endothelial function in aged diabetic and high-fat fed rats,” British Journal of Pharmacology, vol. 153, no. 5, pp. 894–906, 2008. View at Publisher · View at Google Scholar · View at Scopus
  103. W.-J. Zhang and B. Frei, “α-Lipoic acid inhibits TNF-α-induced NF-κB activation and adhesion molecule expression in human aortic endothelial cells,” The FASEB Journal, vol. 15, no. 13, pp. 2423–2432, 2001. View at Publisher · View at Google Scholar · View at Scopus
  104. M. B. Gomes and C. A. Negrato, “Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases,” Diabetology & Metabolic Syndrome, vol. 6, no. 1, p. 80, 2014. View at Publisher · View at Google Scholar
  105. S. Vasdev, C. A. Ford, S. Parai, L. Longerich, and V. Gadag, “Dietary α-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats,” Journal of Hypertension, vol. 18, no. 5, pp. 567–573, 2000. View at Publisher · View at Google Scholar · View at Scopus
  106. K. P. Shay, R. F. Moreau, E. J. Smith, A. R. Smith, and T. M. Hagen, “Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential,” Biochimica et Biophysica Acta, vol. 1790, no. 10, pp. 1149–1160, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. T. J. Kizhakekuttu and M. E. Widlansky, “Natural antioxidants and hypertension: promise and challenges,” Cardiovascular Therapeutics, vol. 28, no. 4, pp. e20–e32, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. C. J. McMackin, M. E. Widlansky, N. M. Hamburg et al., “Effect of combined treatment with α-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease,” The Journal of Clinical Hypertension, vol. 9, no. 4, pp. 249–255, 2007. View at Publisher · View at Google Scholar · View at Scopus
  109. S. Ozbal, B. U. Ergur, G. Erbil, I. Tekmen, A. Bagryank, and Z. Cavdar, “The effects of α-lipoic acid against testicular ischemia-reperfusion injury in rats,” The Scientific World Journal, vol. 2012, Article ID 489248, 8 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  110. A. Frank, M. Bonney, S. Bonney, L. Weitzel, M. Koeppen, and T. Eckle, “Myocardial ischemia reperfusion injury: from basic science to clinical bedside,” Seminars in Cardiothoracic and Vascular Anesthesia, vol. 16, no. 3, pp. 123–132, 2012. View at Publisher · View at Google Scholar · View at Scopus
  111. E. A. Aiello, R. I. Jabr, and W. C. Cole, “Arrhythmia and delayed recovery of cardiac action potential during reperfusion after ischemia: role of oxygen radical-induced no-reflow phenomenon,” Circulation Research, vol. 77, no. 1, pp. 153–162, 1995. View at Publisher · View at Google Scholar · View at Scopus
  112. M. Dudek, J. Knutelska, M. Bednarski et al., “Alpha lipoic acid protects the heart against myocardial post ischemia-reperfusion arrhythmias via KATP channel activation in isolated rat hearts,” Pharmacological Reports, vol. 66, no. 3, pp. 499–504, 2014. View at Publisher · View at Google Scholar · View at Scopus
  113. C. Deng, Z. Sun, G. Tong et al., “α-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway,” PLoS ONE, vol. 8, no. 3, Article ID e58371, 2013. View at Publisher · View at Google Scholar · View at Scopus
  114. Y.-F. Tian, C.-T. He, Y.-T. Chen, and P.-S. Hsieh, “Lipoic acid suppresses portal endotoxemia-induced steatohepatitis and pancreatic inflammation in rats,” World Journal of Gastroenterology, vol. 19, no. 18, pp. 2761–2771, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. M. Gomes and C. Negrato, “Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases,” Diabetology & Metabolic Syndrome, vol. 6, article 80, 2014. View at Publisher · View at Google Scholar
  116. M. Bayeva, M. Gheorghiade, and H. Ardehali, “Mitochondria as a therapeutic target in heart failure,” Journal of the American College of Cardiology, vol. 61, no. 6, pp. 599–610, 2013. View at Publisher · View at Google Scholar · View at Scopus
  117. H. Ardehali, H. N. Sabbah, M. A. Burke et al., “Targeting myocardial substrate metabolism in heart failure: potential for new therapies,” European Journal of Heart Failure, vol. 14, no. 2, pp. 120–129, 2012. View at Publisher · View at Google Scholar · View at Scopus
  118. D. B. Sawyer, “Oxidative stress in heart failure: what are we missing?” The American Journal of the Medical Sciences, vol. 342, no. 2, pp. 120–124, 2011. View at Publisher · View at Google Scholar · View at Scopus
  119. C.-J. Li, L. Lv, H. Li, and D.-M. Yu, “Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid,” Cardiovascular Diabetology, vol. 11, article 73, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. L. Packer and E. Cadenas, “Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling,” Journal of Clinical Biochemistry and Nutrition, vol. 48, no. 1, pp. 26–32, 2011. View at Publisher · View at Google Scholar · View at Scopus
  121. I. Padmalayam, “Targeting mitochondrial oxidative stress through Lipoic acid synthase: a novel strategy to manage diabetic cardiovascular disease,” Cardiovascular and Hematological Agents in Medicinal Chemistry, vol. 10, no. 3, pp. 223–233, 2012. View at Publisher · View at Google Scholar · View at Scopus
  122. S. Subramanian, B. Kalyanaraman, and R. Q. Migrino, “Mitochondrially targeted antioxidants for the treatment of cardiovascular diseases,” Recent Patents on Cardiovascular Drug Discovery, vol. 5, no. 1, pp. 54–65, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. C.-J. Li, Q.-M. Zhang, M.-Z. Li, J.-Y. Zhang, P. Yu, and D.-M. Yu, “Attenuation of myocardial apoptosis by alpha-lipoic acid through suppression of mitochondrial oxidative stress to reduce diabetic cardiomyopathy,” Chinese Medical Journal, vol. 122, no. 21, pp. 2580–2586, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. Z. Cao, M. Tsang, H. Zhao, and Y. Li, “Induction of endogenous antioxidants and phase 2 enzymes by α-lipoic acid in rat cardiac H9C2 cells: protection against oxidative injury,” Biochemical and Biophysical Research Communications, vol. 310, no. 3, pp. 979–985, 2003. View at Publisher · View at Google Scholar · View at Scopus
  125. H. Huk-Kolega, B. Skibska, P. Kleniewska, A. Piechota, Ł. Michalski, and A. Gora̧ca, “Role of lipoic acld in health and disease,” Polski Merkuriusz Lekarski, vol. 31, no. 183, pp. 183–185, 2011. View at Google Scholar · View at Scopus