Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2021 / Article
Special Issue

Oxidative Stress, Senescence, and Nutrition in Age-Related Diseases

View this Special Issue

Review Article | Open Access

Volume 2021 |Article ID 5523516 | https://doi.org/10.1155/2021/5523516

Du Xiang, Yang Liu, Shujun Zhou, Encheng Zhou, Yanfeng Wang, "Protective Effects of Estrogen on Cardiovascular Disease Mediated by Oxidative Stress", Oxidative Medicine and Cellular Longevity, vol. 2021, Article ID 5523516, 15 pages, 2021. https://doi.org/10.1155/2021/5523516

Protective Effects of Estrogen on Cardiovascular Disease Mediated by Oxidative Stress

Academic Editor: Stefania D’Adamo
Received25 Jan 2021
Revised16 May 2021
Accepted22 May 2021
Published29 Jun 2021

Abstract

Perimenopause is an important stage of female senescence. Epidemiological investigation has shown that the incidence of cardiovascular disease in premenopausal women is lower than that in men, and the incidence of cardiovascular disease in postmenopausal women is significantly higher than that in men. This phenomenon reveals that estrogen has a definite protective effect on the cardiovascular system. In the cardiovascular system, oxidative stress is considered important in the pathogenesis of atherosclerosis, myocardial dysfunction, cardiac hypertrophy, heart failure, and myocardial ischemia. From the perspective of oxidative stress, estrogen plays a regulatory role in the cardiovascular system through the estrogen receptor, providing strategies for the treatment of menopausal women with cardiovascular diseases.

1. Introduction

Cardiovascular disease (CVD) has the highest mortality in the world [1]. With the aging of the population and the increasing incidence of obesity and diabetes, the cost of treatment for CVD will significantly increase worldwide [2]. The incidence of CVD is related to gender, and premenopausal women have a lower incidence of hypertension, atherosclerosis, myocardial dysfunction, ventricular hypertrophy, heart failure, and myocardial ischemia than age-matched men [3]. However, the advantage in women gradually disappears after menopause, which leads to a higher risk of CVD in postmenopausal women than men of the same age. This trend is largely attributed to the role of female estrogen in this process [4]. During the transitional period of menopause, women suffer from blood vessel aging, decreased diastolic ability, insulin sensitivity, and increased blood pressure due to decreased ovarian function and changes in hormone secretion, which increase the risk of CVD development [5]. Several studies have shown that certain functions mediated by estrogen in the cardiovascular system are related to the reduction in local oxidative stress (OS), which can reduce reactive oxygen species (ROS) by regulating the production of ROS enzymes and can enhance ROS clearance [6].

Estrogen has a wide range of critical physiological effects and exerts crucial effects on the growth and maturation of the endocrine, cardiovascular, skeletal, and metabolic systems [7]. With the extension of the human life span, the population of China is gradually aging; so, women will live nearly one-third of their lives without estrogen protection [8]. The decline in the ovarian function and the reduction in estrogen during menopause usually result in physical and psychological changes in females and lead to a series of autonomic dysfunction symptoms (sweating, irritability, insomnia, hot flashes, etc.) [9]. In addition, heart and brain vascular diseases, osteoporosis, and low immunity, which are related to menopause, have become the main risk factors affecting women’s quality of life and life span [10].

Cells are involved in a variety of oxidation reactions in physiological processes, which inevitably leads to the release of ROS and reactive nitrogen species (RNS) [11]. If the balance between ROS and the antioxidant defense mechanism is broken, the accumulated ROS thereby destroy cell macromolecules, cause cell dysfunction, and ultimately kill cells [12]. In the cardiovascular system, excessive ROS production is considered one of the pathogenic mechanisms of atherosclerosis, myocardial dysfunction, myocardial hypertrophy, heart failure, and myocardial ischemia [13]. Reducing the accumulation of ROS in cells, therefore, is a potential strategy to prevent and treat CVD [14]. Estrogen and the body’s antioxidant ability decreases as menopausal women grow older, while the body’s nicotinamide adenine dinucleotide phosphate (NADPH) and other oxidase activities increase, which results in an inability to clear ROS in time [15]. The accumulated ROS then induce OS, leading to osteoporosis and CVD [16]. Nevertheless, the specific mechanism of how estrogen alleviates CVD remains unclear. This article mainly summarizes the protective effects of estrogen on the cardiovascular system and its mechanism from the perspective of OS, laying the foundation for the treatment of cardiovascular disease in menopausal women.

2. Estrogen

Estrogen is a fat-soluble steroid hormone and plays an essential role in the development and physiology of many organ systems, including the breasts, uterus, bone, and cardiovascular system [17]. Estrogen is mainly produced by cholesterol in the ovaries, corpus luteum, and placenta in premenopausal women, with a small amount of estrogen produced by nonovarian organs, such as the liver, heart, skin, and brain [18]. There are three types of estrogen that have been found in the human body: estrone (E1), 17β-estradiol (E2), and estriol (E3) [19]. Among these types, E2 has the strongest biological activity [20]. E1 is synthesized by adrenal dehydroepiandrosterone in the adipose tissue and is more important after menopause; E2, the main product of the entire biosynthesis process, is the most effective estrogen before menopause; E3, which is produced by E1 formed by 16a-hydroxylation, is the weakest estrogen and plays a significant role during pregnancy [21]. In prepubertal women and postmenopausal women, estrogen produced by extragonadal tissues acts locally by paracrine or endocrine means to maintain tissue-specific functions [18]. Estrogen produced by follicles is synthesized by the granulosa cells and inner membrane cells of the follicle under the synergistic effects of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [18]. Androstenedione and testosterone produced by the inner membrane cells of the follicle under the action of LH diffuse into the granular cells through the basement membrane [22]. Aromatase activity is enhanced under the effects of FSH [23]. Then, androstenedione is converted into estrone, and testosterone is converted into estradiol, which is known as the two-cell-two gonadotropin theory of estrogen synthesis [24]. A small part of the synthesized estrogen enters the follicular cavity, and the majority enter the blood, regulating the differentiation and growth of target cells, such as the endometrium and breasts.

Estrogen inactivation can occur through metabolism, including conversion of E2 to less active E1 or E3 and sulfation by estrogen sulfatase from E2 to 17β-estradiol-1,3,5-triene-3,17-diol 3-sulfate, so that it no longer interacts with estrogen receptors [25]. In addition, the lack of a new adipose-derived cytokine lipocalin-2 in female mice can limit E2 production by downregulating aromatase in the adipose tissue [26]. Therefore, the aromatase that controls the production of estrogen in the body can maintain a dynamic balance between estrogen synthesis and inactivation [27].

3. Estrogen Receptor (ER)

The ER is the core target of estrogen to exert its regulatory function and affects diseases in many organ systems including the cardiovascular system and skeletal system [28]. Most human estrogen receptors (ERs) are ligand-dependent transcription factors that belong to the steroid family. Two ERs have been discovered so far: the classic nuclear estrogen receptor (nER) and the membrane estrogen receptor (mER) [29]. The nER has two subtypes: ERα and ERβ [30]. ERα, which was discovered by Elwood Jenson in 1958, is widely distributed and has high mRNA expression in the uterus, testes, ovaries, prostate, skeletal muscle, kidneys, skin, etc. [31] In 1996, Kuiper et al. [32] isolated the second nuclear estrogen receptor, ERβ, which has higher mRNA expression in the ovaries, colon, brain tissue, kidneys, and male reproductive system. With further indepth study of nER, it was found that some target cells can quickly respond to estrogen without ER [33]. Therefore, in addition to the classical nER-mediated slow pathway, there are also fast membrane receptor-mediated estrogen effects that are mediated by G protein-coupled estrogen receptors (GPERs), including G-protein coupled receptor 30 (GPR30) and ER-X [34]. GPR30 is expressed in many brain regions (the hypothalamus, hippocampus, cortex, etc.), the adrenal medulla, renal pelvis, and ovaries [35]. The expression of ER-X is strictly regulated during development, and it is expressed in the brain of fetal baboons and the cerebral cortex, uterus, and lungs of rodents after birth. In adults, ER-X is rarely expressed but is expressed after ischemic injury [36].

4. Action Mode of Estrogen

The ER structure is mainly divided into five domains: transcription activation region-1 (AF-1), the DNA-binding domain, the ligand-binding domain (LBD), the hinge region, and transcription activation region-2 (AF-2) [37]. Each domain has its specific function, and the LBD is the key area where the ligand recognizes and binds the receptor and then triggers its effects [38]. Most signal pathways mediated by estrogen are regulated by ERs, which can be divided into genomic and nongenomic effects according to whether they are transcriptionally regulated [39]. The classic mode of estrogen action is the genomic effect mechanism in which estrogen enters the nucleus and combines with nuclear ERs to form a dimer, and then the estrogen-receptor complex binds to estrogen response elements and further regulates the gene expression and corresponding proteins, which triggers a series of cascade reaction events [40]. The nongenomic effect does not depend on the gene expression regulation mechanism, and its mode of action is that estrogen binds to the estrogen receptor on the cell membrane and activates the corresponding signal transduction, causing related responses to exert the effects of estrogen [41]. The genomic effect generally works slowly, as it takes several hours to several days to occur, while the nongenomic effect typically only takes a few seconds to a few minutes, which is relatively fast [42]. The nongenomic effect mainly relies on the G protein-coupled estrogen receptor (GPER/GPR30), which was discovered in recent years. GPER, a member of the G protein-coupled receptor superfamily, is composed of 375 amino acids with a molecular weight of about 40 000 [43]. GPER is distributed in various organs and tissues, including breast, ovary, uterus, cardiovascular system, and lung and bone tissue, and is widely involved in the occurrence and development of estrogen-related diseases such as malignant tumors, inflammatory reactions, CVD, and obesity [44, 45]. The combination of E2 and GPER promotes the dissociation of the G protein trimer structure into α, β, and γ subunits [46]. The α subunit catalyzes cyclic adenosine monophosphate (cAMP) by activating adenylate cyclase on the cell membrane, and cAMP activates protein kinase A (PKA), thereby rapidly regulating cellular function changes [4749]. In addition, β and γ subunits promote the release of heparin binding epidermal growth factor like growth factor (HBEGF) and the binding to epidermal growth factor receptor (EGFR), leading to the activation of multiple signal factors including mitogen activated protein kinase (MAPKs), phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB/Akt), and extracellular signal-regulated kinase (ERK1/2), which indirectly regulates the transcriptional activity of related genes and exerts various biological effects in the cell [47, 5052] (Figure 1).

5. Oxidative Stress

The human body constantly produces oxygen free radicals during normal daily metabolic processes and approximately 95% of which are ROS, including superoxide anions (O2-), hydrogen peroxide (H2O2), hydroxyl free radicals (-OH), and peroxynitrite (ONOO-) [53]. Normally, the body’s oxidation system and the antioxidant defense system maintain a dynamic balance. When the antioxidant and oxidative effects are out of balance, pathological damage occurs. This process is called OS [6]. The main sources of intracellular ROS include xanthine oxidase, lipoxygenases, cyclooxygenases, peroxidases, uncoupled nitric oxide (NO) synthases, NADPH, the mitochondrial respiratory chain, and heme-containing proteins, and among these, an abnormal mitochondrial respiratory chain is the main source of ROS [54]. When the mitochondria cannot undergo normal oxidative phosphorylation, many ROS are produced [55, 56]. The generated ROS damage organelles, such as the mitochondria and plasma membrane and the DNA, proteins, and lipids of the organelle components, which eventually leads to cell death, aggravate the production of mitochondrial ROS and form a vicious circle [57, 58]. Finally, tissue cell dysfunction, such as endothelial cell dysfunction, vasculitis, and the accumulation of low-density lipoprotein in the arterial wall, is triggered. In addition, ROS are not only potentially harmful products of metabolism [59]. They can also act as second messengers to regulate cell growth and apoptosis [60]. The intracellular antioxidant defense system includes superoxide dismutases (SOD), catalase (CAT), glutathione peroxidases (GPx), and other nonenzymatic antioxidants, such as reduced glutathione (GSH), vitamin C, vitamin E, β-carotene, ubiquinone, lipoic acid, and flavonoids, which can inhibit the formation of ROS or reduce the damage caused by ROS [6163]. Therefore, new treatments involve not only eliminating ROS but also inhibiting the activity of ROS-generating enzymes.

There is an important relationship between sex and OS. Studies have demonstrated that male rats have a higher degree of OS than female rats [64]. Another in vivo study showed that young men have higher OS biochemical markers than women of the same age [3]. In addition, clinical and experimental data show that women have greater antioxidant potential than men [65]. In summary, there is a critical relationship between gender and OS [65, 66]. Women are not susceptible to OS and have stronger antioxidative stress capabilities than men, which further demonstrate that there is a strong connection between female estrogen and antioxidants [3].

6. Cardiovascular Diseases Mediated by OS after Menopause

After menopause, due to the exhaustion of ovarian follicles, the production of estrogen is greatly reduced, and the production of extraovarian estrogen becomes dominant [67]. During this period, the main plasma estrogen is estrone, which is less effective than E2 [68]. Premenopausal women have higher levels of NO, which protects the heart and inhibits smooth muscle proliferation in heart disease [38]. After menopause, due to the decrease in estradiol antioxidants, postmenopausal women are more likely to undergo OS than women of reproductive age, and the incidence of CVD increases [69]. Moreover, the significant reduction in estrogen increases the level of free fatty acids, which makes postmenopausal women more likely to develop metabolic syndrome and insulin resistance, which are considered risk factors for CVD [70, 71].

OS is the main cause of many age-related cardiovascular pathologies, including ischemia/reperfusion (IR), hypertensive heart disease, and heart failure [72]. Under physiological conditions, low levels of ROS produced by mitochondria play an important role in vascular endothelial cells, which are involved in the production of NO, regulation of cell apoptosis, and signal transduction [73]. Some signaling pathways that promote aging, mainly including ASK1-p38-MAPK, ASK1-SAPK/JNK, and ASK1-NFkB, are involved in menopause [74]. These signaling pathways are also involved in oxidative stress-mediated CVD. The ASK1 signal body is a high-molecular weight protein complex composed of ROS-sensitive inhibitor protein and activator protein [74]. Its molecular weight is approximately 1500 kDa, which regulates the response to ROS and the signaling networks that promote aging and age-associated diseases of OS [74, 75]. The ROS related to aging mainly originate from mitochondrial dysfunction [76]. The generated ROS can activate the p38-MAPK and SAPK/JNK pathways, thereby mediating the occurrence of CVD [74]. In an aging mouse model, the inhibition of OS delayed aging through the p38-MAPK pathway, which means these signaling pathways have a certain relationship with aging, OS, and CVD [77] (Figure 2). The mechanism by which ROS mediate CVD is introduced below.

6.1. Oxidative Stress and Hypertrophic Cardiomyopathy (HCM)

HCM is characterized by left ventricular hypertrophy, a reduced ventricular cavity and limited ventricular filling [78, 79]. In HCM, Ca2+ in myocardial cells in combination with myofilaments can reduce the concentration of Ca2+ in the mitochondria, the activity of mitochondrial tricarboxylic acid cycle enzymes, and the level of reduced coenzyme I/II, thereby triggering OS [80]. In addition, excessive production of mitochondrial ROS leads to activation of Ca2+ channels and transporters in cardiomyocytes, which activates transcription factors related to cardiomyocyte hypertrophy [79]. Cardiomyocyte hypertrophy can lead to excessive production of mitochondrial ROS, and excessive ROS can cause cardiomyocyte hypertrophy, thus forming a vicious circle [81]. A previous study confirmed that E2 reduced myocardial OS and improved myocardial diastolic function, prevented myocardial energy dysregulation, thereby improving HCM [82].

6.2. Oxidative Stress and Atherosclerosis

Atherosclerosis is the leading cause of CVD [83]. Increasing evidence showed that the activation of proinflammatory signals, the expression of cytokines/chemokines, and OS are important factors leading to the occurrence of atherosclerosis [84]. Harmful stimuli (such as dyslipidemia, hypertension and smoking) can cause endothelial cell dysfunction, promote the expression of adhesion factors and chemotactic molecules, and increase the permeability of macromolecules [85]. This activity facilitates LDL entry into the arterial wall, resulting in apolipoprotein B100 and extracellular matrix (ECM) proteoglycan binding and retention [85]. In addition, oxidized low-density lipoprotein (OxLDL) activates endothelial cells to release phospholipids [86]. NOX2 is a specific subtype of NADPH oxidases (NOXs) and has been identified to play a key role in atherosclerosis formation [87]. NOX2 deficiency has little effect on blood lipids, but it can reduce the formation of aortic superoxide, increase the bioavailability of NO, and reduce the formation of atherosclerotic plaques [88]. Judkins et al. [89] found that in knockout apolipoprotein E (Apo E -/-) mice, the expression of NOX2 in mouse aortic endothelial cells and macrophages increases before atherosclerosis, and these changes are consistent with the increase in aortic superoxide production. Therefore, this study clearly showed that NOX2 plays a key role in superoxide generation, NO bioavailability reduction, and atherosclerotic plaque formation [90]. In conclusion, OS plays an important role in the progression of atherosclerosis. There is increasing evidence suggested that age is an important risk factor for atherosclerosis, which is promoted by cellular senescence [91]. E2 retarded oxidized low-density lipoprotein-induced premature senescence, thereby inhibiting arterial aging and the development of atherosclerosis [92].

6.3. Oxidative Stress and Heart Failure (HF)

HF is the terminal stage of heart disease. Many experiments and clinical studies have shown that ROS production is related to the pathogenesis of HF [93, 94]. By activating transcription factors and G-protein coupled receptors (GPCRs), ROS can stimulate myocardial cell growth and matrix remodeling and accelerate cell dysfunction [95]. The effects of H2O2 on adult rat ventricular myocytes are concentration-dependent [96, 97]. Low H2O2 concentrations can cause cardiomyocyte hypertrophy by activating ERK1/2, while high H2O2 concentrations can activate JNK and cause cardiomyocyte apoptosis [98]. ROS can also affect the extracellular matrix, stimulate the proliferation of cardiac fibroblasts, and activate matrix metalloproteinases (MMPs), which are the basic effects leading to fibrosis and matrix remodeling [99]. MMPs play an important role in the process of normal tissue remodeling, such as cell migration, invasion, proliferation, and apoptosis and have been shown to be elevated in HF [100]. MMPs are usually secreted in an inactive form and are activated by ROS after translation [100]. Hayashidani et al. [101] have shown that the survival rate of MMP-2 knockout mice after myocardial infarction (MI) is significantly improved because knocking out MMP-2 reduces the incidence of early heart rupture and left ventricular remodeling and failure. Kinugawa et al. [102] explored the role of OS in left ventricular remodeling and failure after myocardial infarction in mice and whether the -OH scavenger dimethylthiourea can alleviate these changes, and compared with untreated mice, mice who received dimethylthiourea demonstrated inhibition of MMP-2 activation, significantly improved left ventricular contractility, and reduced left ventricular hypertrophy. These findings indicate that OS products can stimulate the activation of myocardial MMP, and MMP plays a decisive role in left ventricular remodeling, thereby participating in the development of heart failure [103].

In recent years, OS markers, such as 8-OHdG, which has attracted much attention, have increasingly been used to assist in the diagnosis of heart failure [104]. These markers cause oxidative damage to DNA and serve as biomarkers of endogenous and exogenous factors [105]. The interaction between advanced glycation end products (AGEs) and their receptors (RAGE) initiates a series of signal cascade reactions, activating the transcription factor NF-κB and leading to the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF), and eventually inducing OS; so, AGEs and RAGE are considered OS markers [106]. Another marker, neopterin, is mainly produced by macrophages after γ-interferon stimulation [107]. The higher the neopterin concentration, the higher the NYHA heart function classification, and the higher the probability of CVD. In addition, neopterin is related to the formation of ROS. In summary, biomarkers of OS can be used as reliable indicators for the diagnosis of heart failure [95]. The development of HF is characterized by increased OS in cardiomyocytes. The increased production of ROS correlates with the progression of HF [108]. E2 treatment improves HF by antioxidative mechanisms, and E2 may be an effective adjunctive therapy for patients with HF [109].

6.4. Oxidative Stress and Hypertension

Hypertension is the most common chronic disease, and it is a major risk factor for CVD. OS is a contributing factor in the pathogenesis of hypertension [65]. Excessive OS and a weakened ability to scavenge free radicals can lead to hypertension. Although the sources of intracellular ROS are diverse, the activity of NOXs is the main source of ROS [110]. There are five subtypes of NOXs: NOX1, NOX2, NOX3, NOX4, and NOX5 [111]. In the vasculature, different cells and blood vessels express different NOX subtypes, and there is no specific NOX subtype. NOX4 is mainly expressed in endothelial cells and vascular smooth muscle cells [112]. NOX1 is mainly expressed in large blood vessels, while NOX2 is mainly expressed in resistance blood vessels [103]. In the vasculature, ROS is mainly produced by vascular endothelial cells, adventitia cells, and smooth muscle cells, and it is mainly the NADPH enzyme that produces O2- under the stimulation of angiotensin II (Ang II) and endothelin-1 [113]. The generated ROS can act as second messengers in the cell, increasing the intracellular concentration of Ca2+, causing vasoconstriction, thereby promoting the development of hypertension [114].

The endothelium is a type of highly active monolayer that plays an important role in regulating vascular wall tension, cell adhesion, thrombosis, smooth muscle cell proliferation, and vascular inflammation [115]. All of these roles are achieved by releasing endothelium-derived relaxing factors, such as prostaglandins, nitric oxide, endothelium-derived hyperpolarizing factors, and endothelium-derived contractile factors [1]. The generated vasodilating factor NO is rapidly degraded by the oxygen free radical O2-, and the superoxide anion produced by NOX reacts with NO to create peroxynitrite, which reduces the bioavailability of NO and causes vasoconstriction [103]. Therefore, hypertension is related to a decrease in NO and an increase in OS. Ang II is the main bioactive peptide of the renin-angiotensin system (RAS), which plays an important role in vasoconstriction, hypertrophy, fibrosis, inflammation, and aging [116]. Ang II activates the Ang II type 1 (AT1R) and type 2 (AT2R) receptors and drives OS through membrane-bound NADPH to increase the production of O2- [117]. The mechanisms by which Ang II mediates its physiological and pathophysiological vascular effects are complex [116, 118]. Previous studies have shown that ROS production and activation of reduction-oxidation dependent signaling cascades play key roles in Ang II-induced actions [119]. ROS is produced by various types of vascular cells, including endothelial cells, smooth muscle cells, outer membrane fibroblasts, and resident macrophages [120]. The main source of ROS in vascular cells is nonphagocytic NADPH oxidase, which is regulated by vasoactive agents (including Ang II) [121]. Rajagopalan et al. [122] found that long-term infusion of Ang II increases the oxidase activity of NADPH so that hypertension can be reduced. Some common antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor inhibitors, can reduce blood pressure by inhibiting NOXs and reducing the production of ROS [120]. Hypertension susceptibility in women increases at the transition to menopause, and altered estrogen signaling is implicated in the increased hypertension incidence associated with menopause [123]. ER-β signaling plays an important role in blood pressure regulation. The inhibition of increased NMDA receptor signaling and ROS production in ER-β neurons in the paraventricular nucleus of the hypothalamus can reduce the susceptibility to hypertension [124].

6.5. Oxidative Stress and Atrial Fibrillation (AF)

AF is the most common arrhythmia in clinical settings. Many experiments have confirmed the role of OS in the pathogenesis of AF [125, 126]. By inducing cardiomyocyte hypertrophy and apoptosis, ROS have a destructive effect on calcium transport channels in cardiomyocytes, leading to arrhythmias and enhancing cardiac remodeling [127]. The atrial type 2 ryanodine receptor (RyR2) has been shown to be a target of OS and is involved in the pathogenesis of AF [128]. The abnormality of intracellular Ca2+ plays an important role in the occurrence of AF [128]. RyR2 is the main calcium release channel in atrial myocytes, and it can become dysfunctional due to OS [129]. The increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity can increase the susceptibility of AF [128]. Thus, changing intracellular Ca2+ homeostasis is related to the pathogenesis of AF. Studies have shown that reducing the production of ROS can decrease the release of atrial Ca2+ during diastole, which hinders the development of AF [130]. Due to the low efficiency of DNA proofreading and repair, human mitochondrial DNA is prone to oxidative damage and mutation during replication. Lin et al. [131] speculated that increased OS and mitochondrial DNA mutation may be related to AF. Polymerase chain reaction (PCR) analysis showed that the probability of mitochondrial DNA deletion in the atrial muscle of patients with AF was 3.75 times higher than that of patients without AF, and the level of oxidative damage to DNA in patients with AF was also higher than that in patients without AF [131]. Dudley et al. [132] used a swine model of AF to further confirm that OS is related to the pathogenesis of AF. In addition, Bretler et al. [133] indicated that E2 therapy was associated with a decreased risk of new-onset AF especially among . E2 therapy can reduce the risk of AF by 9-37 percent, the first year after myocardial infarction.

6.6. Oxidative Stress and Ischemic Cardiomyopathy (ICM)

ICM refers to the clinical syndrome of chronic myocardial ischemia caused by coronary atherosclerosis, leading to diffuse fibrosis of myocardium and loss of myocardial function [134]. It is one of the most common causes of end-stage heart failure. Previous studies have shown that OS is closely related to the occurrence and development of ICM [135, 136]. During the pathogenesis of ICM, ischemia and hypoxia trigger a series of physiological and pathological processes, which make ROS accumulate in cells and promote OS [135]. The excessive production of ROS or the reduction of ROS clearance can damage the cell structure, destroy the cell membrane through lipid peroxidation, impair the function of enzymes through the oxidation of proteins, and cause chromosome damage through nucleic acid base modification and chain rupture, thus causing cell dysfunction [137]. In the process of ICM, ROS can destroy the cell membrane during the ICM process, promote calcium overload, cell apoptosis and the production of inflammatory mediators, and damage the function of endothelial cells and platelets, thereby promoting the occurrence and development of ICM [135, 138141].

7. Estrogen Inhibits Oxidative Stress

OS is associated with a variety of diseases, including heart failure, hypertension, and atherosclerosis. Therefore, OS is an important mechanism of CVD, and any gender differences related to OS may affect the pathogenesis of CVD [3]. Estrogen may not be the only cause of gender differences between men and women but further research is needed to determine the protective effects of estrogen and the mechanisms involved. Jeanes et al. [142] found that E2 and ERα-specific agonists decreased the infarct size by reducing myocardial lipid peroxidation during I/R in rats. In a hypoxia and reoxygenation model of rat cardiomyocytes in vitro, E2 reduced cardiomyocyte apoptosis and ROS production by decreasing MAPK activity [143]. Estrogen decreases the risk of CVD by downregulating inflammatory markers, such as chemokines and cell adhesion molecules, to fight atherosclerosis [144]. In addition, it can stabilize atherosclerotic plaques by reducing the expression of matrix metalloproteinases and the production of plasminogen activator inhibitor-1 (PAI-1) [145]. Moreover, high concentrations of estrogen promote vasodilation by producing prostacyclin, inhibiting endothelin synthesis and blocking calcium channels [1]. In addition to its benefits to the cardiovascular system, estrogen also has an effect on biomarkers of vascular activity [146]. For example, a study concerning normal postmenopausal women revealed that taking estrogen for one year significantly reduced catecholamine levels, mean blood pressure, and low-density lipoprotein (LDL), while increasing nitrite and nitrate levels [147149]. Other studies on the effects of estrogen on OS have shown that serum lipid peroxides decrease, and the overall antioxidant status is upregulated [150]. Estrogen increases binding proteins produced by the liver, such as sex hormone binding globulin, water maintenance, and sodium balance in the body, and it distributes lipids by increasing high-density lipoprotein (HDL) and reducing LDL [151]. It is clear that there is a definite relationship between estrogen and OS (as shown in Table 1).


MechanismsThe changes in oxidative stressReferences

E2 decreased MAPK activityThe cardiomyocyte apoptosis and ROS production were reduced[74, 77, 143, 180]
Estrogen decreased serum lipid peroxidesOverall antioxidant status was upregulated[92, 150, 173, 181]
E2 inhibited NOX subunit p47phoxThe reduction of superoxide anion production was inhibited[155, 160]
E2 decreased NOX subunits gp91phox, p22phox, and p67phox induced by Ang IIROS production was reduced[143, 158, 182, 183]
E2 upregulated the expression and activity of SOD induced by Ang IIROS production wad reduced[167, 184190]
Estrogen restored antioxidant enzymes GPX1 and GPX4 expression levelsOxidative stress balance was maintained[158, 181, 189]
Estrogen increased the expression of the glutathione rate-limiting enzyme γ-glutamylcysteine synthetaseOxidative stress balance was maintained[168, 190, 191]
Estrogen maintained the bioavailability of NO by increasing the expression of eNOS mRNA and proteinThe production of NO increased and oxidative stress was reduced[84, 192195]
ERα activated eNOS through the PI3/AKT signal pathwayThe production of NO increased and oxidative stress was reduced[175, 189, 195]
Estrogen increased the intracellular availability of the eNOS cofactor BH4 and prevented the uncoupling of eNOSThe production of eNOS-dependent ROS was reduced[177, 178]

Some studies have shown that estrogen inhibits OS in cardiac vessels and the myocardium by reducing local ROS production and increasing ROS clearance [143]. In addition, the removal of ROS in the blood vessel wall and heart is essential to ensure the structural and functional integrity of the cardiovascular system. NOXs is the main source of ROS [152]. Estrogen regulates the expression of NOXs subunits in different models, which has a protective effect on the cardiovascular system [153]. NOXs is an oxidase complex composed of NOX1-5, dual oxidase, and regulatory subunits p22phox, p47phox, p67phox, p40phox, and Racl [111, 154]. Supplementation of E2 in ovariectomized rats inhibited the reduction of superoxide anion production by the NOX subunit p47phox [155]. This finding suggested that estrogen changes the production of superoxide anions by regulating the expression or activity of NOXs in vascular smooth muscle cells [156]. Ang II can increase the expression of Rac1 protein in vascular smooth muscle cells, while E2 can restore it to normal levels [157]. Zhang et al. [158] found that the expression of p22phox increased in salt-sensitive ovariectomized rats that were fed a high-sodium diet, which was reversed by injection of estrogen. Estrogen can also reduce the expression of the NOXs subunit NOX2 in endothelial cells in a time- and concentration-dependent manner, and this effect can be blocked by ER antagonists [159]. To summarize, both estrogen deficiency and estrogen supplementation change the expression and activity of NOXs, thus changing the production of O2- [160]. However, due to the different regulation of NOXs subunits in different animals and cells, it is not completely clear how estrogen affects the activity of NOXs through complex mechanisms (as shown in Table 1).

The renin-angiotensin-aldosterone system (RAAS) is an important humoral regulatory system composed of some peptide hormones and corresponding enzymes, which mainly maintain and regulate the balance of blood pressure, water, and electrolytes and maintain human homeostasis [161]. In vivo and in vitro studies have demonstrated that the RAAS plays a key role in the pathogenesis of CVD [162]. Ang II activates the AT1R and mediates most of the biological effects of Ang II, such as vasoconstriction, aldosterone release, sodium and water maintenance, and cell growth. AT1R-related NOXs produce many highly active O2- molecules, which are the main source of RAAS-induced ROS production, in monocytes, macrophages, endothelial cells, and vascular smooth muscle cells [163]. In addition, estrogen deficiency can also increase the expression of the angiotensin converting enzyme (ACE), thus promoting the production of Ang II [164]. Nickenig et al. [165] found that estrogen deficiency can upregulate AT1R in isolated vascular smooth muscle, while estrogen supplementation can reverse this phenomenon. The expression of NOXs subunits gp91phox, p22phox, and p67phox induced by Ang II are decreased by E2 [143] (as shown in Table 1).

SOD, which converts O2- into H2O2, is a cellular antioxidant defense mechanism and has been shown to be regulated by steroids [166]. Strehlow et al. [167] found that E2 upregulated the expression and activity of SOD in vascular smooth muscle cells induced by Ang II, thus inhibiting the production of ROS induced by angiotensin converting enzyme II. In ovariectomized rats, the expression of antioxidant enzymes GPX1 and GPX4 significantly decreased, but estrogen returned expression to normal values [158]. Estrogen can also increase the expression of the glutathione rate-limiting enzyme γ-glutamylcysteine synthetase, which is consistent with the activation of glutathione reductase promoter activity by ERβ-specific cis-acting elements [168] (as shown in Table 1).

Nitric oxide synthase (eNOS) produced by endothelial cells can produce the vasodilator NO, and NO spreads to vascular smooth muscle cells, activates guanylate cyclase, and increases cyclic guanosine monophosphate (cGMP) [84]. NO plays a direct role in tissue oxygen balance, organ perfusion, vascular remodeling, and metabolic requirements by regulating vascular tension and diameter [169]. Kauser et al. [170] first found that there were gender differences in the production and release of NO, and the release of NO in the aorta of female rats was higher than that of males. Estrogen maintains the bioavailability of NO by increasing the expression of eNOS mRNA and protein, thus increasing the production of NO in endothelial cells and vascular smooth muscle cells [171]. Wassmann et al. [172] demonstrated that raloxifene, a selective estrogen receptor modulator, increases the bioavailability of NO by upregulating eNOS mRNA and activity in the aorta of spontaneously hypertensive rats. Estrogen deficiency can increase blood pressure, produce OS, and decrease NO production. Similarly, estrogen supplementation increased NO production and decreased the amount of lipid peroxidation in ovariectomized rats [173]. However, Barbacanne et al. [174] believe that the antioxidant effects of estrogen are not achieved by affecting the activity or expression of eNOS but by directly decreasing the production of O2-. In vivo and in vitro experiments demonstrated that estrogen produces NO through nongenomic effects, and the specific mechanism is that ERα activates eNOS through the PI3/AKT signal pathway to produce NO. [175] Wong et al. [176] confirmed that raloxifene can increase the phosphorylation of eNOS and Akt in rat aortae and protect endocrine cells from OS. Estrogen can also increase the intracellular availability of the eNOS cofactor BH4 and prevent the uncoupling of eNOS, thus preventing the production of eNOS-dependent ROS [177] (as shown in Table 1). To summarize, estrogen can be used as a potential mechanism of antioxidation by increasing the production of NO, reducing O2-, and increasing the utilization of cofactor BH4 [178]. To support this hypothesis, postmenopausal women taking BH4 can improve endothelial dysfunction and reduce the incidence of atherosclerosis [179].

8. Conclusion

The incidence of CVD is lower in premenopausal women than in men of the same age, but it significantly increases after menopause. This phenomenon shows that estrogen has a protective effect on the cardiovascular system, which is undeniable. OS is an important mechanism of cardiovascular disease. This article mainly indicates the protection of estrogen in cardiovascular disease from the perspective of OS. When postmenopausal women are treated with estrogen, a comprehensive assessment should be performed according to the patient’s symptoms, CVD and breast cancer risk, etc. to determine the route of administration, dosage, and frequency, and the risks and benefits should be regularly assessed to obtain minimal risk and maximal benefit through individualized treatment.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Du Xiang and Yang Liu are contributed equally and share first authorship. Du Xiang and Yang Liu and Yanfeng Wang designed, searched, and wrote the paper. Shujun Zhou and Encheng Zhou revised the paper. Yanfeng Wang is responsible for the critical revision and final approval.

Acknowledgments

The manuscript is supported by the Science and Technology Innovation Incubation Fund of Zhongnan Hospital of Wuhan University (ZNJC201923).

References

  1. Y. B. Somani, J. A. Pawelczyk, M. J. de Souza, P. M. Kris-Etherton, and D. N. Proctor, “Aging women and their endothelium: probing the relative role of estrogen on vasodilator function,” American Journal of Physiology Heart and Circulatory Physiology, vol. 317, no. 2, pp. H395–H404, 2019. View at: Publisher Site | Google Scholar
  2. D. Lin, L. Wang, S. Yan, Q. Zhang, J. H. Zhang, and A. Shao, “The role of oxidative stress in common risk factors and mechanisms of cardio- cerebrovascular ischemia and depression,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 2491927, 13 pages, 2019. View at: Publisher Site | Google Scholar
  3. M. C. Kander, Y. Cui, and Z. Liu, “Gender difference in oxidative stress: a new look at the mechanisms for cardiovascular diseases,” Journal of Cellular and Molecular Medicine, vol. 21, no. 5, pp. 1024–1032, 2017. View at: Publisher Site | Google Scholar
  4. L. Newson, “Menopause and cardiovascular disease,” Post Reproductive Health, vol. 24, no. 1, pp. 44–49, 2018. View at: Publisher Site | Google Scholar
  5. S. Patel, A. Homaei, A. B. Raju, and B. R. Meher, “Estrogen: the necessary evil for human health, and ways to tame it,” Biomedicine & Pharmacotherapy, vol. 102, pp. 403–411, 2018. View at: Publisher Site | Google Scholar
  6. P. Pignatelli, D. Menichelli, D. Pastori, and F. Violi, “Oxidative stress and cardiovascular disease: new insights,” Kardiologia Polska, vol. 76, no. 4, pp. 713–722, 2018. View at: Publisher Site | Google Scholar
  7. E. Morselli, R. S. Santos, A. Criollo, M. D. Nelson, B. F. Palmer, and D. J. Clegg, “The effects of oestrogens and their receptors on cardiometabolic health,” Nature Reviews Endocrinology, vol. 13, no. 6, pp. 352–364, 2017. View at: Publisher Site | Google Scholar
  8. T. Laisk, O. Tšuiko, T. Jatsenko et al., “Demographic and evolutionary trends in ovarian function and aging,” Human Reproduction Update, vol. 25, no. 1, pp. 34–50, 2019. View at: Publisher Site | Google Scholar
  9. P. Monteleone, G. Mascagni, A. Giannini, A. R. Genazzani, and T. Simoncini, “Symptoms of menopause -- global prevalence, physiology and implications,” Nature Reviews. Endocrinology, vol. 14, no. 4, pp. 199–215, 2018. View at: Publisher Site | Google Scholar
  10. S. D. Sullivan, P. M. Sarrel, and L. M. Nelson, “Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause,” Fertility and Sterility, vol. 106, no. 7, pp. 1588–1599, 2016. View at: Publisher Site | Google Scholar
  11. E. Niki, “Oxidant-specific biomarkers of oxidative stress. Association with atherosclerosis and implication for antioxidant effects,” Free Radical Biology & Medicine, vol. 120, pp. 425–440, 2018. View at: Publisher Site | Google Scholar
  12. J. Luo, K. Mills, S. le Cessie, R. Noordam, and D. van Heemst, “Ageing, age-related diseases and oxidative stress: what to do next?” Ageing Research Reviews, vol. 57, article 100982, 2020. View at: Publisher Site | Google Scholar
  13. A. Manea, A. Fortuno, and J. L. Martin-Ventura, “Oxidative stress in cardiovascular pathologies: genetics, cellular, and molecular mechanisms and future antioxidant therapies,” Oxidative Medicine and Cellular Longevity, vol. 2012, Article ID 373450, 3 pages, 2012. View at: Publisher Site | Google Scholar
  14. Y. Zhang, P. Murugesan, K. Huang, and H. Cai, “NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets,” Nature Reviews Cardiology, vol. 17, no. 3, pp. 170–194, 2020. View at: Publisher Site | Google Scholar
  15. N. T. Moldogazieva, I. M. Mokhosoev, T. I. Mel’nikova, Y. B. Porozov, and A. A. Terentiev, “Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 3085756, 14 pages, 2019. View at: Publisher Site | Google Scholar
  16. N. N. Wu, Y. Zhang, and J. Ren, “Mitophagy, mitochondrial dynamics, and homeostasis in cardiovascular aging,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 9825061, 15 pages, 2019. View at: Publisher Site | Google Scholar
  17. C. L. Faltas, K. A. Lebron, and M. K. Holz, “Unconventional estrogen signaling in health and disease,” Endocrinology, vol. 161, no. 4, 2020. View at: Publisher Site | Google Scholar
  18. R. Barakat, O. Oakley, H. Kim, J. Jin, and C. M. J. Ko, “Extra-gonadal sites of estrogen biosynthesis and function,” BMB Reports, vol. 49, no. 9, pp. 488–496, 2016. View at: Publisher Site | Google Scholar
  19. J. Cui, Y. Shen, and R. Li, “Estrogen synthesis and signaling pathways during aging: from periphery to brain,” Trends in Molecular Medicine, vol. 19, no. 3, pp. 197–209, 2013. View at: Publisher Site | Google Scholar
  20. L. Medzikovic, L. Aryan, and M. Eghbali, “Connecting sex differences, estrogen signaling, and microRNAs in cardiac fibrosis,” Journal of Molecular Medicine, vol. 97, no. 10, pp. 1385–1398, 2019. View at: Publisher Site | Google Scholar
  21. C. Lee, J. Kim, and Y. Jung, “Potential therapeutic application of estrogen in gender disparity of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis,” Cell, vol. 8, no. 10, p. 1259, 2019. View at: Publisher Site | Google Scholar
  22. A. Biegon, N. Alia-Klein, D. L. Alexoff et al., “Relationship of estrogen synthesis capacity in the brain with obesity and self-control in men and women,” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 37, pp. 22962–22966, 2020. View at: Publisher Site | Google Scholar
  23. P. Cooke, M. K. Nanjappa, C. M. Ko, G. S. Prins, and R. A. Hess, “Estrogens in male physiology,” Physiological Reviews, vol. 97, no. 3, pp. 995–1043, 2017. View at: Publisher Site | Google Scholar
  24. Z. Shoham and M. Schachter, “Estrogen biosynthesis--regulation, action, remote effects, and value of monitoring in ovarian stimulation cycles,” Fertility and Sterility, vol. 65, no. 4, pp. 687–701, 1996. View at: Publisher Site | Google Scholar
  25. Y. L. Chen, H. Y. Fu, T. H. Lee et al., “Estrogen degraders and estrogen degradation pathway identified in an activated sludge,” Applied and Environmental Microbiology, vol. 84, no. 10, 2018. View at: Publisher Site | Google Scholar
  26. P. Kamble, M. J. Pereira, K. Almby, and J. W. Eriksson, “Estrogen interacts with glucocorticoids in the regulation of lipocalin 2 expression in human adipose tissue. Reciprocal roles of estrogen receptor α and β in insulin resistance?” Molecular and Cellular Endocrinology, vol. 490, pp. 28–36, 2019. View at: Publisher Site | Google Scholar
  27. M. Khan, R. Ullah, S. U. Rehman et al., “17β-estradiol modulates SIRT1 and halts oxidative stress-mediated cognitive impairment in a male aging mouse model,” Cell, vol. 8, no. 8, p. 928, 2019. View at: Publisher Site | Google Scholar
  28. T. Luo and J. K. Kim, “The role of estrogen and estrogen receptors on cardiomyocytes: an overview,” Canadian Journal of Cardiology, vol. 32, no. 8, pp. 1017–1025, 2016. View at: Publisher Site | Google Scholar
  29. L. Jiao, J. O.’. Machuki, Q. Wu et al., “Estrogen and calcium handling proteins: new discoveries and mechanisms in cardiovascular diseases,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 318, no. 4, pp. H820–H829, 2020. View at: Publisher Site | Google Scholar
  30. S. Novella, D. Pérez-Cremades, A. Mompeón, and C. Hermenegildo, “Mechanisms underlying the influence of oestrogen on cardiovascular physiology in women,” The Journal of Physiology, vol. 597, no. 19, pp. 4873–4886, 2019. View at: Publisher Site | Google Scholar
  31. J. Russell, C. K. Jones, and P. A. Newhouse, “The role of estrogen in brain and cognitive aging,” Neurotherapeutics, vol. 16, no. 3, pp. 649–665, 2019. View at: Publisher Site | Google Scholar
  32. G. Kuiper, E. Enmark, M. Pelto-Huikko, S. Nilsson, and J. A. Gustafsson, “Cloning of a novel receptor expressed in rat prostate and ovary,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 12, pp. 5925–5930, 1996. View at: Publisher Site | Google Scholar
  33. C. Thomas and J. A. Gustafsson, “The different roles of ER subtypes in cancer biology and therapy,” Nature Reviews Cancer, vol. 11, no. 8, pp. 597–608, 2011. View at: Publisher Site | Google Scholar
  34. A. Knowlton and A. R. Lee, “Estrogen and the cardiovascular system,” Pharmacology & Therapeutics, vol. 135, no. 1, pp. 54–70, 2012. View at: Publisher Site | Google Scholar
  35. J. Xiang, X. Liu, J. Ren et al., “How does estrogen work on autophagy?” Autophagy, vol. 15, no. 2, pp. 197–211, 2019. View at: Publisher Site | Google Scholar
  36. R. Kiyama and Y. Wada-Kiyama, “Estrogenic endocrine disruptors: molecular mechanisms of action,” Environment International, vol. 83, pp. 11–40, 2015. View at: Publisher Site | Google Scholar
  37. E. Tunc, A. A. Eve, and Z. Madak-Erdogan, “Coronary microvascular dysfunction and estrogen receptor signaling,” Trends in Endocrinology & Metabolism, vol. 31, no. 3, pp. 228–238, 2020. View at: Publisher Site | Google Scholar
  38. P. Gourdy, M. Guillaume, C. Fontaine et al., “Estrogen receptor subcellular localization and cardiometabolism,” Molecular Metabolism, vol. 15, pp. 56–69, 2018. View at: Publisher Site | Google Scholar
  39. K. Ueda, Y. Adachi, P. Liu, N. Fukuma, and E. Takimoto, “Regulatory actions of estrogen receptor signaling in the cardiovascular system,” Frontiers in Endocrinology, vol. 10, 2020. View at: Publisher Site | Google Scholar
  40. A. Iorga, C. M. Cunningham, S. Moazeni, G. Ruffenach, S. Umar, and M. Eghbali, “The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy,” Biology of Sex Differences, vol. 8, no. 1, p. 33, 2017. View at: Publisher Site | Google Scholar
  41. N. Fuentes and P. Silveyra, “Estrogen receptor signaling mechanisms,” Advances in Protein Chemistry and Structural Biology, vol. 116, pp. 135–170, 2019. View at: Publisher Site | Google Scholar
  42. S. Hewitt, “Estrogen receptors: new directions in the new millennium,” Endocrine Reviews, vol. 39, no. 5, pp. 664–675, 2018. View at: Publisher Site | Google Scholar
  43. D. Rosenbaum, S. G. F. Rasmussen, and B. K. Kobilka, “The structure and function of G-protein-coupled receptors,” Nature, vol. 459, no. 7245, pp. 356–363, 2009. View at: Publisher Site | Google Scholar
  44. M. S. Alavi, A. Shamsizadeh, H. Azhdari-Zarmehri, and A. Roohbakhsh, “Orphan G protein-coupled receptors: the role in CNS disorders,” Biomedicine & Pharmacotherapy, vol. 98, pp. 222–232, 2018. View at: Publisher Site | Google Scholar
  45. M. Barton, “Not lost in translation: emerging clinical importance of the G protein-coupled estrogen receptor GPER,” Steroids, vol. 111, pp. 37–45, 2016. View at: Publisher Site | Google Scholar
  46. W. Weis and B. K. Kobilka, “The molecular basis of G protein-coupled receptor activation,” Annual Review of Biochemistry, vol. 87, no. 1, pp. 897–919, 2018. View at: Publisher Site | Google Scholar
  47. E. J. Filardo, “Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30: a novel signaling pathway with potential significance for breast cancer,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 80, no. 2, pp. 231–238, 2002. View at: Publisher Site | Google Scholar
  48. J. K. Tan, C. McKenzie, E. Mariño, L. Macia, and C. R. Mackay, “Metabolite-sensing G protein-coupled receptors-facilitators of diet-related immune regulation,” Annual Review of Immunology, vol. 35, no. 1, pp. 371–402, 2017. View at: Publisher Site | Google Scholar
  49. E. Filardo, J. A. Quinn, A. R. Frackelton Jr., and K. I. Bland, “Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis,” Molecular Endocrinology, vol. 16, no. 1, pp. 70–84, 2002. View at: Publisher Site | Google Scholar
  50. D. Wootten, A. Christopoulos, M. Marti-Solano, M. M. Babu, and P. M. Sexton, “Mechanisms of signalling and biased agonism in G protein-coupled receptors,” Nature reviews Molecular Cell Biology, vol. 19, no. 10, pp. 638–653, 2018. View at: Publisher Site | Google Scholar
  51. J. Bopassa, M. Eghbali, L. Toro, and E. Stefani, “A novel estrogen receptor GPER inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 298, no. 1, pp. H16–H23, 2010. View at: Publisher Site | Google Scholar
  52. A. Trenti, S. Tedesco, C. Boscaro, L. Trevisi, C. Bolego, and A. Cignarella, “Estrogen, angiogenesis, immunity and cell metabolism: solving the puzzle,” International Journal of Molecular Sciences, vol. 19, no. 3, p. 859, 2018. View at: Publisher Site | Google Scholar
  53. D. Galaris, A. Barbouti, and K. Pantopoulos, “Iron homeostasis and oxidative stress: an intimate relationship,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, vol. 1866, no. 12, article 118535, 2019. View at: Publisher Site | Google Scholar
  54. J. Peoples, A. Saraf, N. Ghazal, T. T. Pham, and J. Q. Kwong, “Mitochondrial dysfunction and oxidative stress in heart disease,” Experimental & Molecular Medicine, vol. 51, no. 12, pp. 1–13, 2019. View at: Publisher Site | Google Scholar
  55. D. Arauna, M. Furrianca, Y. Espinosa-Parrilla, E. Fuentes, M. Alarcón, and I. Palomo, “Natural bioactive compounds as protectors of mitochondrial dysfunction in cardiovascular diseases and aging,” Molecules, vol. 24, no. 23, p. 4259, 2019. View at: Publisher Site | Google Scholar
  56. I. Lejri, A. Grimm, and A. Eckert, “Mitochondria, estrogen and female brain aging,” Frontiers in Aging Neuroscience, vol. 10, p. 124, 2018. View at: Publisher Site | Google Scholar
  57. C. Cadeddu Dessalvi, A. Pepe, C. Penna et al., “Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens,” Heart Failure Reviews, vol. 24, no. 6, pp. 915–925, 2019. View at: Publisher Site | Google Scholar
  58. T. Liu, N. Li, Y. Q. Yan et al., “Recent advances in the anti-aging effects of phytoestrogens on collagen, water content, and oxidative stress,” Phytotherapy Research, vol. 34, no. 3, pp. 435–447, 2020. View at: Publisher Site | Google Scholar
  59. M. Vernier, C. R. Dufour, S. McGuirk et al., “Estrogen-related receptors are targetable ROS sensors,” Genes & Development, vol. 34, no. 7-8, pp. 544–559, 2020. View at: Publisher Site | Google Scholar
  60. B. Zhou, J. Y. Zhang, X. S. Liu et al., “Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis,” Cell Research, vol. 28, no. 12, pp. 1171–1185, 2018. View at: Publisher Site | Google Scholar
  61. S. B. Doshi and A. Agarwal, “The role of oxidative stress in menopause,” Journal of Mid-life Health, vol. 4, no. 3, pp. 140–146, 2013. View at: Publisher Site | Google Scholar
  62. E. Barati, H. Nikzad, and M. Karimian, “Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management,” Cellular and Molecular Life Sciences, vol. 77, no. 1, pp. 93–113, 2020. View at: Publisher Site | Google Scholar
  63. M. Maciejczyk, A. Zalewska, and J. R. Ładny, “Salivary antioxidant barrier, redox status, and oxidative damage to proteins and lipids in healthy children, adults, and the elderly,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 4393460, 12 pages, 2019. View at: Publisher Site | Google Scholar
  64. J. Barp, A. S. R. Araújo, T. R. G. Fernandes et al., “Myocardial antioxidant and oxidative stress changes due to sex hormones,” Brazilian Journal of Medical and Biological Research, vol. 35, no. 9, pp. 1075–1081, 2002. View at: Publisher Site | Google Scholar
  65. J. Reckelhoff, D. G. Romero, and L. L. Yanes Cardozo, “Sex, oxidative stress, and hypertension: insights from animal models,” Physiology, vol. 34, no. 3, pp. 178–188, 2019. View at: Publisher Site | Google Scholar
  66. I. Pinchuk, D. Weber, B. Kochlik et al., “Gender- and age-dependencies of oxidative stress, as detected based on the steady state concentrations of different biomarkers in the MARK-AGE study,” Redox Biology, vol. 24, article 101204, 2019. View at: Publisher Site | Google Scholar
  67. P. May-Panloup, L. Boucret, J. M. Chao de la Barca et al., “Ovarian ageing: the role of mitochondria in oocytes and follicles,” Human Reproduction Update, vol. 22, no. 6, pp. 725–743, 2016. View at: Publisher Site | Google Scholar
  68. R. Qureshi, M. Picon-Ruiz, I. Aurrekoetxea-Rodriguez et al., “The major pre- and postmenopausal estrogens play opposing roles in obesity- driven mammary inflammation and Breast cancer development,” Cell Metabolism, vol. 31, no. 6, pp. 1154–1172.e9, 2020. View at: Publisher Site | Google Scholar
  69. A. Díaz, R. López-Grueso, J. Gambini et al., “Sex differences in age-associated type 2 diabetes in rats—role of estrogens and oxidative stress,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 6734836, 13 pages, 2019. View at: Publisher Site | Google Scholar
  70. C. Keck and M. Taylor, “Emerging research on the implications of hormone replacement therapy on coronary heart disease,” Current Atherosclerosis Reports, vol. 20, no. 12, 2018. View at: Publisher Site | Google Scholar
  71. S. R. El Khoudary, “HDL and the menopause,” Current Opinion in Lipidology, vol. 28, no. 4, pp. 328–336, 2017. View at: Publisher Site | Google Scholar
  72. T. Xu, W. Ding, X. Ji et al., “Oxidative stress in cell death and cardiovascular diseases,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 9030563, 11 pages, 2019. View at: Publisher Site | Google Scholar
  73. T. Nakamura, I. Naguro, and H. Ichijo, “Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases,” Biochimica et Biophysica Acta - General Subjects, vol. 1863, no. 9, pp. 1398–1409, 2019. View at: Publisher Site | Google Scholar
  74. J. Papaconstantinou, “The role of signaling pathways of inflammation and oxidative stress in development of senescence and aging phenotypes in cardiovascular disease,” Cell, vol. 8, no. 11, p. 1383, 2019. View at: Publisher Site | Google Scholar
  75. C. Morales Betanzos, J. D. Federspiel, A. M. Palubinsky, B. A. McLaughlin, and D. C. Liebler, “Dynamic phosphorylation of apoptosis signal regulating kinase 1 (ASK1) in response to oxidative and electrophilic stress,” Chemical Research in Toxicology, vol. 29, no. 12, pp. 2175–2183, 2016. View at: Publisher Site | Google Scholar
  76. 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 Site | Google Scholar
  77. C. Hsieh, J. I. Rosenblatt, and J. Papaconstantinou, “Age-associated changes in SAPK/JNK and p38 MAPK signaling in response to the generation of ROS by 3-nitropropionic acid,” Mechanisms of Ageing and Development, vol. 124, no. 6, pp. 733–746, 2003. View at: Publisher Site | Google Scholar
  78. E. Rowin, A. Hausvater, M. S. Link et al., “Clinical profile and consequences of atrial fibrillation in hypertrophic cardiomyopathy,” Circulation, vol. 136, no. 25, pp. 2420–2436, 2017. View at: Publisher Site | Google Scholar
  79. P. Wijnker, V. Sequeira, D. W. D. Kuster, and J. Velden, “Hypertrophic cardiomyopathy: a vicious cycle triggered by sarcomere mutations and secondary disease hits,” Antioxidants & Redox Signaling, vol. 31, no. 4, pp. 318–358, 2019. View at: Publisher Site | Google Scholar
  80. J. Gilda and A. V. Gomes, “Proteasome dysfunction in cardiomyopathies,” The Journal of Physiology, vol. 595, no. 12, pp. 4051–4071, 2017. View at: Publisher Site | Google Scholar
  81. D. Zhang, Y. Li, D. Heims-Waldron et al., “Mitochondrial cardiomyopathy caused by elevated reactive oxygen species and impaired cardiomyocyte proliferation,” Circulation Research, vol. 122, no. 1, pp. 74–87, 2018. View at: Publisher Site | Google Scholar
  82. Y. Chen, Z. Zhang, F. Hu et al., “17β-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function: a preclinical study in a mouse model of a human hypertrophic cardiomyopathy mutation,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 147, pp. 92–102, 2015. View at: Publisher Site | Google Scholar
  83. E. Sanchez-Rodriguez, A. Egea-Zorrilla, J. Plaza-Díaz et al., “The gut microbiota and its implication in the development of atherosclerosis and related cardiovascular diseases,” Nutrients, vol. 12, no. 3, p. 605, 2020. View at: Publisher Site | Google Scholar
  84. U. Förstermann, 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
  85. A. M. Giudetti, M. Salzet, and T. Cassano, “Oxidative stress in aging brain: nutritional and pharmacological interventions for neurodegenerative disorders,” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 3416028, 2 pages, 2018. View at: Publisher Site | Google Scholar
  86. P. Marchio, S. Guerra-Ojeda, J. M. Vila, M. Aldasoro, V. M. Victor, and M. D. Mauricio, “Targeting early atherosclerosis: a focus on oxidative stress and inflammation,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 8563845, 32 pages, 2019. View at: Publisher Site | Google Scholar
  87. A. J. Kattoor, N. V. K. Pothineni, D. Palagiri, and J. L. Mehta, “Oxidative stress in atherosclerosis,” Current Atherosclerosis Reports, vol. 19, no. 11, 2017. View at: Publisher Site | Google Scholar
  88. A. Maqbool, N. T. Watt, N. Haywood et al., “Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance-related vascular damage,” American Journal of Physiology. Cell Physiology, vol. 319, no. 1, pp. C64–C74, 2020. View at: Publisher Site | Google Scholar
  89. C. Judkins, H. Diep, B. R. S. Broughton et al., “Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE-/- mice,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 298, no. 1, pp. H24–H32, 2010. View at: Publisher Site | Google Scholar
  90. P. P. Sfyri, N. Y. Yuldasheva, A. Tzimou et al., “Attenuation of oxidative stress-induced lesions in skeletal muscle in a mouse model of obesity-independent hyperlipidaemia and atherosclerosis through the inhibition of Nox2 activity,” Free Radical Biology & Medicine, vol. 129, pp. 504–519, 2018. View at: Publisher Site | Google Scholar
  91. J. Wang and M. Bennett, “Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence,” Circulation Research, vol. 111, no. 2, pp. 245–259, 2012. View at: Publisher Site | Google Scholar
  92. Y. Sasaki, Y. Ikeda, T. Miyauchi, Y. Uchikado, Y. Akasaki, and M. Ohishi, “Estrogen-SIRT1 Axis plays a pivotal role in protecting arteries against menopause-induced senescence and atherosclerosis,” Journal of Atherosclerosis and Thrombosis, vol. 27, no. 1, pp. 47–59, 2020. View at: Publisher Site | Google Scholar
  93. L. A. Kiyuna, R. P. Albuquerque, C. H. Chen, D. Mochly-Rosen, and J. C. B. Ferreira, “Targeting mitochondrial dysfunction and oxidative stress in heart failure: challenges and opportunities,” Free Radical Biology and Medicine, vol. 129, pp. 155–168, 2018. View at: Publisher Site | Google Scholar
  94. M. S. Ali Sheikh, U. Salma, B. Zhang, J. Chen, J. Zhuang, and Z. Ping, “Diagnostic, prognostic, and therapeutic value of circulating miRNAs in heart failure patients associated with oxidative stress,” Oxidative Medicine and Cellular Longevity, vol. 2016, 13 pages, 2016. View at: Publisher Site | Google Scholar
  95. A. van der Pol, W. van Gilst, A. A. Voors, and P. van der Meer, “Treating oxidative stress in heart failure: past, present and future,” European Journal of Heart Failure, vol. 21, no. 4, pp. 425–435, 2019. View at: Publisher Site | Google Scholar
  96. Y. Li, J. Xia, N. Jiang et al., “Corin protects H2O2-induced apoptosis through PI3K/AKT and NF-κB pathway in cardiomyocytes,” Biomedicine & Pharmacotherapy, vol. 97, pp. 594–599, 2018. View at: Publisher Site | Google Scholar
  97. B. Liu, N. Jia, H. L. Wei, M. Lan, J. M. Liu, and Y. Z. Xue, “Knockdown of p66ShcA activates Nrf2 pathway to protect cardiomyocytes from oxidative stress and inflammation induced by H2O2,” European Review for Medical and Pharmacological Sciences, vol. 24, no. 12, pp. 6994–7001, 2020. View at: Publisher Site | Google Scholar
  98. S. Kwon, D. R. Pimentel, A. Remondino, D. B. Sawyer, and W. S. Colucci, “H2O2 regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways,” Journal of Molecular and Cellular Cardiology, vol. 35, no. 6, pp. 615–621, 2003. View at: Publisher Site | Google Scholar
  99. K. Ayoub, N. V. K. Pothineni, J. Rutland, Z. Ding, and J. L. Mehta, “Immunity, inflammation, and oxidative stress in heart failure: emerging molecular targets,” Cardiovascular Drugs and Therapy, vol. 31, no. 5-6, pp. 593–608, 2017. View at: Publisher Site | Google Scholar
  100. D. Siwik and W. S. Colucci, “Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium,” Heart Failure Reviews, vol. 9, no. 1, pp. 43–51, 2004. View at: Publisher Site | Google Scholar
  101. S. Hayashidani, H. Tsutsui, M. Ikeuchi et al., “Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 285, no. 3, pp. H1229–H1235, 2003. View at: Publisher Site | Google Scholar
  102. S. Kinugawa, H. Tsutsui, S. Hayashidani et al., “Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress,” Circulation Research, vol. 87, no. 5, pp. 392–398, 2000. View at: Publisher Site | Google Scholar
  103. 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
  104. M. A. Sánchez-Rodríguez and V. M. Mendoza-Núñez, “Oxidative stress indexes for diagnosis of health or disease in humans,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 4128152, 32 pages, 2019. View at: Publisher Site | Google Scholar
  105. M. Graille, P. Wild, J. J. Sauvain, M. Hemmendinger, I. Guseva Canu, and N. B. Hopf, “Urinary 8-OHdG as a biomarker for oxidative stress: a systematic literature review and meta-analysis,” International Journal of Molecular Sciences, vol. 21, no. 11, p. 3743, 2020. View at: Publisher Site | Google Scholar
  106. A. Bierhaus, P. M. Humpert, M. Morcos et al., “Understanding RAGE, the receptor for advanced glycation end products,” Journal of Molecular Medicine, vol. 83, no. 11, pp. 876–886, 2005. View at: Publisher Site | Google Scholar
  107. J. Razumovitch, G. N. Semenkova, D. Fuchs, and S. N. Cherenkevich, “Influence of neopterin on the generation of reactive oxygen species in human neutrophils,” FEBS Letters, vol. 549, no. 1-3, pp. 83–86, 2003. View at: Publisher Site | Google Scholar
  108. A. Sabbatini and G. Kararigas, “Menopause-related estrogen decrease and the pathogenesis of HFpEF:,” Journal of the American College of Cardiology, vol. 75, no. 9, pp. 1074–1082, 2020. View at: Publisher Site | Google Scholar
  109. M. Satoh, C. M. Matter, H. Ogita et al., “Inhibition of apoptosis-regulated signaling kinase-1 and prevention of congestive heart failure by estrogen,” Circulation, vol. 115, no. 25, pp. 3197–3204, 2007. View at: Publisher Site | Google Scholar
  110. H. Y. Small, S. Migliarino, M. Czesnikiewicz-Guzik, and T. J. Guzik, “Hypertension: focus on autoimmunity and oxidative stress,” Free Radical Biology & Medicine, vol. 125, pp. 104–115, 2018. View at: Publisher Site | Google Scholar
  111. G. A. Knock, “NADPH oxidase in the vasculature: expression, regulation and signalling pathways; role in normal cardiovascular physiology and its dysregulation in hypertension,” Free Radical Biology and Medicine, vol. 145, pp. 385–427, 2019. View at: Publisher Site | Google Scholar
  112. K. Bedard and K. H. Krause, “The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology,” Physiological Reviews, vol. 87, no. 1, pp. 245–313, 2007. View at: Publisher Site | Google Scholar
  113. C. S. Wilcox, C. Wang, and D. Wang, “Endothelin-1-induced microvascular ROS and contractility in angiotensin-II-infused mice depend on COX and TP receptors,” Antioxidants, vol. 8, no. 6, p. 193, 2019. View at: Publisher Site | Google Scholar
  114. R. Brito, G. Castillo, J. González, N. Valls, and R. Rodrigo, “Oxidative stress in hypertension: mechanisms and therapeutic opportunities,” Experimental and Clinical Endocrinology & Diabetes, vol. 123, no. 6, pp. 325–335, 2015. View at: Publisher Site | Google Scholar
  115. P. Thakore and S. Earley, “Transient receptor potential channels and endothelial cell calcium signaling,” Comprehensive Physiology, vol. 9, no. 3, pp. 1249–1277, 2019. View at: Publisher Site | Google Scholar
  116. S. Forrester, G. W. Booz, C. D. Sigmund et al., “Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology,” Physiological Reviews, vol. 98, no. 3, pp. 1627–1738, 2018. View at: Publisher Site | Google Scholar
  117. A. Nguyen Dinh Cat, A. C. Montezano, D. Burger, and R. M. Touyz, “Angiotensin II, NADPH oxidase, and redox signaling in the vasculature,” Antioxidants & Redox Signaling, vol. 19, no. 10, pp. 1110–1120, 2013. View at: Publisher Site | Google Scholar
  118. S. Das, E. Zhang, P. Senapati et al., “A novel angiotensin II-induced long noncoding RNA giver regulates oxidative stress, inflammation, and proliferation in vascular smooth muscle cells,” Circulation Research, vol. 123, no. 12, pp. 1298–1312, 2018. View at: Publisher Site | Google Scholar
  119. K. Griendling, D. Sorescu, and M. Ushio-Fukai, “NAD(P)H oxidase: role in cardiovascular biology and disease,” Circulation Research, vol. 86, no. 5, pp. 494–501, 2000. View at: Publisher Site | Google Scholar
  120. R. Touyz, “Reactive oxygen species and angiotensin II signaling in vascular cells: implications in cardiovascular disease,” Brazilian Journal of Medical and Biological Research, vol. 37, no. 8, pp. 1263–1273, 2004. View at: Publisher Site | Google Scholar
  121. A. C. Montezano and R. M. Touyz, “Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies,” Ann Med, vol. 44, no. sup1, pp. S2–S16, 2012. View at: Publisher Site | Google Scholar
  122. S. Rajagopalan, S. Kurz, T. Münzel et al., “Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone,” The Journal of Clinical Investigation, vol. 97, no. 8, pp. 1916–1923, 1996. View at: Publisher Site | Google Scholar
  123. K. Srivaratharajah and B. L. Abramson, “Hypertension in menopausal women: the effect and role of estrogen,” Menopause, vol. 26, no. 4, pp. 428–430, 2019. View at: Publisher Site | Google Scholar
  124. J. Marques-Lopes, E. Tesfaye, S. Israilov et al., “Redistribution of NMDA receptors in estrogen-receptor-β-containing paraventricular hypothalamic neurons following slow-pressor angiotensin II hypertension in female mice with accelerated ovarian failure,” Neuroendocrinology, vol. 104, no. 3, pp. 239–256, 2017. View at: Publisher Site | Google Scholar
  125. A. Samman Tahhan, P. B. Sandesara, S. S. Hayek et al., “Association between oxidative stress and atrial fibrillation,” Heart Rhythm, vol. 14, no. 12, pp. 1849–1855, 2017. View at: Publisher Site | Google Scholar
  126. L. Emelyanova, Z. Ashary, M. Cosic et al., “Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 311, no. 1, pp. H54–H63, 2016. View at: Publisher Site | Google Scholar
  127. X. Liu, S. Wang, X. Guo et al., “Increased reactive oxygen species–mediated Ca2+/calmodulin-dependent protein kinase II activation contributes to calcium handling abnormalities and impaired contraction in Barth syndrome,” Circulation, vol. 143, no. 19, pp. 1894–1911, 2021. View at: Publisher Site | Google Scholar
  128. M. Chelu, S. Sarma, S. Sood et al., “Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice,” The Journal of Clinical Investigation, vol. 119, no. 7, pp. 1940–1951, 2009. View at: Publisher Site | Google Scholar
  129. M. G. Chelu, S. Sarma, S. Sood et al., “Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice,” Journal of Clinical Investigation, 2009. View at: Publisher Site | Google Scholar
  130. W. Xie, G. Santulli, S. R. Reiken et al., “Mitochondrial oxidative stress promotes atrial fibrillation,” Scientific Reports, vol. 5, no. 1, article 11427, 2015. View at: Publisher Site | Google Scholar
  131. P. Lin, S. H. Lee, C. P. Su, and Y. H. Wei, “Oxidative damage to mitochondrial DNA in atrial muscle of patients with atrial fibrillation,” Free Radical Biology & Medicine, vol. 35, no. 10, pp. 1310–1318, 2003. View at: Publisher Site | Google Scholar
  132. S. Dudley, N. E. Hoch, L. A. McCann et al., “Atrial fibrillation increases production of superoxide by the left atrium and left atrial appendage: role of the NADPH and xanthine oxidases,” Circulation, vol. 112, no. 9, pp. 1266–1273, 2005. View at: Publisher Site | Google Scholar
  133. D. M. Bretler, P. R. Hansen, J. Lindhardsen et al., “Hormone replacement therapy and risk of new-onset atrial fibrillation after myocardial infarction--a nationwide cohort study,” PLoS One, vol. 7, no. 12, article e51580, 2012. View at: Publisher Site | Google Scholar
  134. M. Mahmoudi, M. Yu, V. Serpooshan et al., “Multiscale technologies for treatment of ischemic cardiomyopathy,” Nature Nanotechnology, vol. 12, no. 9, pp. 845–855, 2017. View at: Publisher Site | Google Scholar
  135. S. Neidhardt, J. Garbade, F. Emrich et al., “Ischemic cardiomyopathy affects the thioredoxin system in the human myocardium,” Journal of Cardiac Failure, vol. 25, no. 3, pp. 204–212, 2019. View at: Publisher Site | Google Scholar
  136. I. Muthuramu, R. Amin, A. Postnov et al., “Cholesterol-lowering gene therapy counteracts the development of non-ischemic cardiomyopathy in mice,” Molecular Therapy, vol. 25, no. 11, pp. 2513–2525, 2017. View at: Publisher Site | Google Scholar
  137. D. Tan and T. Suda, “Reactive oxygen species and mitochondrial homeostasis as regulators of stem cell fate and function,” Antioxidants & Redox Signaling, vol. 29, no. 2, pp. 149–168, 2018. View at: Publisher Site | Google Scholar
  138. S. Garcia, D. Grotto, R. P. Bulcão et al., “Evaluation of lipid damage related to pathological and physiological conditions,” Drug and Chemical Toxicology, vol. 36, no. 3, pp. 306–312, 2013. View at: Publisher Site | Google Scholar
  139. Y. W. Wang, J. H. Zhang, Y. Yu, J. Yu, and L. Huang, “Inhibition of store-operated calcium entry protects endothelial progenitor cells from H2O2-induced apoptosis,” Biomolecules & Therapeutics, vol. 24, no. 4, pp. 371–379, 2016. View at: Publisher Site | Google Scholar
  140. D. E. le, M. Pascotto, H. Leong-Poi, I. Sari, A. Micari, and S. Kaul, “Anti-inflammatory and pro-angiogenic effects of beta blockers in a canine model of chronic ischemic cardiomyopathy: comparison between carvedilol and metoprolol,” Basic Research in Cardiology, vol. 108, no. 6, p. 384, 2013. View at: Publisher Site | Google Scholar
  141. D. Pietraforte, R. Vona, A. Marchesi et al., “Redox control of platelet functions in physiology and pathophysiology,” Antioxidants & Redox Signaling, vol. 21, no. 1, pp. 177–193, 2014. View at: Publisher Site | Google Scholar
  142. H. Jeanes, C. Tabor, D. Black, A. Ederveen, and G. A. Gray, “Oestrogen-mediated cardioprotection following ischaemia and reperfusion is mimicked by an oestrogen receptor (ER)α agonist and unaffected by an ERβ antagonist,” The Journal of Endocrinology, vol. 197, no. 3, pp. 493–501, 2008. View at: Publisher Site | Google Scholar
  143. P. Arias-Loza, M. Muehlfelder, and T. Pelzer, “Estrogen and estrogen receptors in cardiovascular oxidative stress,” Pflügers Archiv - European Journal of Physiology, vol. 465, no. 5, pp. 739–746, 2013. View at: Publisher Site | Google Scholar
  144. V. Pelekanou, M. Kampa, F. Kiagiadaki et al., “Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERα36 and GPR30/GPER1,” Journal of Leukocyte Biology, vol. 99, no. 2, pp. 333–347, 2016. View at: Publisher Site | Google Scholar
  145. S.-l. Liu, A. Bajpai, E. A. Hawthorne et al., “Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12,” JCI Insight, vol. 4, no. 1, 2019. View at: Publisher Site | Google Scholar
  146. J. Arnal, F. Lenfant, R. Metivier et al., “Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications,” Physiological Reviews, vol. 97, no. 3, pp. 1045–1087, 2017. View at: Publisher Site | Google Scholar
  147. P. Anagnostis, J. Bitzer, A. Cano et al., “Menopause symptom management in women with dyslipidemias: an EMAS clinical guide,” Maturitas, vol. 135, pp. 82–88, 2020. View at: Publisher Site | Google Scholar
  148. S. Nii, K. Shinohara, H. Matsushita, Y. Noguchi, K. Watanabe, and A. Wakatsuki, “Hepatic effects of estrogen on plasma distribution of small dense low-density lipoprotein and free radical production in postmenopausal women,” Journal of Atherosclerosis and Thrombosis, vol. 23, no. 7, pp. 810–818, 2016. View at: Publisher Site | Google Scholar
  149. N. Hemati, M. Asis, S. Moradi et al., “Effects of genistein on blood pressure: a systematic review and meta-analysis,” Food Research International, vol. 128, article 108764, 2020. View at: Publisher Site | Google Scholar
  150. B. T. Palmisano, L. Zhu, R. H. Eckel, and J. M. Stafford, “Sex differences in lipid and lipoprotein metabolism,” Molecular Metabolism, vol. 15, pp. 45–55, 2018. View at: Publisher Site | Google Scholar
  151. S. H. Ko and H. S. Kim, “Menopause-associated lipid metabolic disorders and foods beneficial for postmenopausal women,” Nutrients, vol. 12, no. 1, p. 202, 2020. View at: Publisher Site | Google Scholar
  152. C. A. Meza, J. D. la Favor, D. H. Kim, and R. C. Hickner, “Endothelial dysfunction: is there a hyperglycemia-induced imbalance of NOX and NOS?” International Journal of Molecular Sciences, vol. 20, no. 15, p. 3775, 2019. View at: Publisher Site | Google Scholar
  153. F. Magnani and A. Mattevi, “Structure and mechanisms of ROS generation by NADPH oxidases,” Current Opinion in Structural Biology, vol. 59, pp. 91–97, 2019. View at: Publisher Site | Google Scholar
  154. A. Tarafdar and G. Pula, “The role of NADPH oxidases and oxidative stress in neurodegenerative disorders,” International Journal of Molecular Sciences, vol. 19, no. 12, p. 3824, 2018. View at: Publisher Site | Google Scholar
  155. M. Florian, A. Freiman, and S. Magder, “Treatment with 17-β-estradiol reduces superoxide production in aorta of ovariectomized rats,” Steroids, vol. 69, no. 13-14, pp. 779–787, 2004. View at: Publisher Site | Google Scholar
  156. P. Zhang, Y. Fu, J. Ju et al., “Estradiol inhibits fMLP-induced neutrophil migration and superoxide production by upregulating MKP-2 and dephosphorylating ERK,” International Immunopharmacology, vol. 75, article 105787, 2019. View at: Publisher Site | Google Scholar
  157. U. Laufs, O. Adam, K. Strehlow et al., “Down-regulation of Rac-1 GTPase by estrogen,” Journal of Biological Chemistry, vol. 278, no. 8, pp. 5956–5962, 2003. View at: Publisher Site | Google Scholar
  158. L. Zhang, S. Fujii, and H. Kosaka, “Effect of oestrogen on reactive oxygen species production in the aortas of ovariectomized dahl salt-sensitive rats,” Journal of Hypertension, vol. 25, no. 2, pp. 407–414, 2007. View at: Publisher Site | Google Scholar
  159. A. Wagner, M. R. Schroeter, and M. Hecker, “17β‐Estradiol inhibition of NADPH oxidase expression in human endothelial cells,” FASEB Journal, vol. 15, no. 12, pp. 2121–2130, 2001. View at: Publisher Site | Google Scholar
  160. M. J. Ronis, M. L. Blackburn, K. Shankar, M. Ferguson, M. A. Cleves, and T. M. Badger, “Estradiol and NADPH oxidase crosstalk regulates responses to high fat feeding in female mice,” Experimental Biology and Medicine, vol. 244, no. 10, pp. 834–845, 2019. View at: Publisher Site | Google Scholar
  161. N. Muñoz-Durango, C. Fuentes, A. Castillo et al., “Role of the renin-angiotensin-aldosterone system beyond blood pressure regulation: molecular and cellular mechanisms involved in end-organ damage during arterial hypertension,” International Journal of Molecular Sciences, vol. 17, no. 7, p. 797, 2016. View at: Publisher Site | Google Scholar
  162. T. von Lueder, D. Atar, and H. Krum, “Current role of neprilysin inhibitors in hypertension and heart failure,” Pharmacology & Therapeutics, vol. 144, no. 1, pp. 41–49, 2014. View at: Publisher Site | Google Scholar
  163. T. M. Paravicini and R. M. Touyz, “NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities,” Diabetes Care, vol. 31, Supplement 2, pp. S170–S180, 2008. View at: Publisher Site | Google Scholar
  164. Z. Zhao, H. Wang, J. A. Jessup, S. H. Lindsey, M. C. Chappell, and L. Groban, “Role of estrogen in diastolic dysfunction,” American Journal of Physiology Heart and Circulatory Physiology, vol. 306, no. 5, pp. H628–H640, 2014. View at: Publisher Site | Google Scholar
  165. G. Nickenig, A. T. Bäumer, C. Grohè et al., “Estrogen modulates AT1Receptor gene expression in vitro and in vivo,” Circulation, vol. 97, no. 22, pp. 2197–2201, 1998. View at: Publisher Site | Google Scholar
  166. L. Juergens, H. Worth, and U. R. Juergens, “New perspectives for mucolytic, anti-inflammatory and adjunctive therapy with 1,8-cineole in COPD and asthma: review on the new therapeutic approach,” Advances in Therapy, vol. 37, no. 5, pp. 1737–1753, 2020. View at: Publisher Site | Google Scholar
  167. K. Strehlow, S. Rotter, S. Wassmann et al., “Modulation of antioxidant enzyme expression and function by estrogen,” Circulation Research, vol. 93, no. 2, pp. 170–177, 2003. View at: Publisher Site | Google Scholar
  168. Y. Urata, Y. Ihara, H. Murata et al., “17β-estradiol protects against oxidative stress-induced cell death through the glutathione/glutaredoxin-dependent redox regulation of Akt in myocardiac H9c2 cells,” Journal of Biological Chemistry, vol. 281, no. 19, pp. 13092–13102, 2006. View at: Publisher Site | Google Scholar
  169. A. Ally, I. Powell, M. M. Ally, K. Chaitoff, and S. M. Nauli, “Role of neuronal nitric oxide synthase on cardiovascular functions in physiological and pathophysiological states,” Nitric Oxide, vol. 102, pp. 52–73, 2020. View at: Publisher Site | Google Scholar
  170. K. Kauser and G. M. Rubanyi, “Gender difference in bioassayable endothelium-derived nitric oxide from isolated rat aortae,” The American Journal of Physiology, vol. 267, 6, Part 2, pp. H2311–H2317, 1994. View at: Publisher Site | Google Scholar
  171. C. Stirone, Y. Chu, L. Sunday, S. P. Duckles, and D. N. Krause, “17β-Estradiol increases endothelial nitric oxide synthase mRNA copy number in cerebral blood vessels: quantification by real-time polymerase chain reaction,” European Journal of Pharmacology, vol. 478, no. 1, pp. 35–38, 2003. View at: Publisher Site | Google Scholar
  172. S. Wassmann, U. Laufs, D. Stamenkovic et al., “Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production,” Circulation, vol. 105, no. 17, pp. 2083–2091, 2002. View at: Publisher Site | Google Scholar
  173. B. Yazğan, Y. Yazğan, İ. S. Övey, and M. Nazıroğlu, “Raloxifene and tamoxifen reduce PARP activity, cytokine and oxidative stress levels in the brain and blood of ovariectomized rats,” Journal of Molecular Neuroscience, vol. 60, no. 2, pp. 214–222, 2016. View at: Publisher Site | Google Scholar
  174. M. Barbacanne, J. Rami, J. B. Michel et al., “Estradiol increases rat aorta endothelium-derived relaxing factor (EDRF) activity without changes in endothelial NO synthase gene expression: possible role of decreased endothelium-derived superoxide anion production,” Cardiovascular Research, vol. 41, no. 3, pp. 672–681, 1999. View at: Publisher Site | Google Scholar
  175. L. Li, K. Hisamoto, K. H. Kim et al., “Variant Estrogen receptor-c-Src molecular interdependence and c-Src structural requirements for endothelial NO synthase activation,” Proceedings of the National Academy of Sciences, vol. 104, no. 42, pp. 16468–16473, 2007. View at: Publisher Site | Google Scholar
  176. C. Wong, L. M. Yung, F. P. Leung et al., “Raloxifene protects endothelial cell function against oxidative stress,” British Journal of Pharmacology, vol. 155, no. 3, pp. 326–334, 2008. View at: Publisher Site | Google Scholar
  177. K. Lam, Y. M. Lee, G. Hsiao, S. Y. Chen, and M. H. Yen, “Estrogen therapy replenishes vascular tetrahydrobiopterin and reduces oxidative stress in ovariectomized rats,” Menopause, vol. 13, no. 2, pp. 294–302, 2006. View at: Publisher Site | Google Scholar
  178. Y. Shah, L. Bass, G. W. Davison et al., “BH4 improves postprandial endothelial function after a high-fat meal in men and postmenopausal women,” Menopause, vol. 24, no. 5, pp. 555–562, 2017. View at: Publisher Site | Google Scholar
  179. G. Douglas, A. B. Hale, J. Patel et al., “Roles for endothelial cell and macrophage Gch1 and tetrahydrobiopterin in atherosclerosis progression,” Cardiovascular Research, vol. 114, no. 10, pp. 1385–1399, 2018. View at: Publisher Site | Google Scholar
  180. J. Kim, A. Pedram, M. Razandi, and E. R. Levin, “Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms,” Journal of Biological Chemistry, vol. 281, no. 10, pp. 6760–6767, 2006. View at: Publisher Site | Google Scholar
  181. J. R. Muñoz-Castañeda, I. Túnez, M. C. Muñoz, I. Bujalance, J. Muntané, and P. Montilla, “Effect of catecholestrogen administration during adriamycin-induced cardiomyopathy in ovariectomized rat,” Free Radical Research, vol. 39, no. 9, pp. 943–948, 2005. View at: Publisher Site | Google Scholar
  182. Q. Yang, C. Wang, Y. Jin et al., “Disocin prevents postmenopausal atherosclerosis in ovariectomized LDLR-/- mice through a PGC-1α/ERα pathway leading to promotion of autophagy and inhibition of oxidative stress, inflammation and apoptosis,” Pharmacological Research, vol. 148, article 104414, 2019. View at: Publisher Site | Google Scholar
  183. A. Debortoli, W. D. N. Rouver, N. T. B. Delgado et al., “GPER modulates tone and coronary vascular reactivity in male and female rats,” Journal of Molecular Endocrinology, vol. 59, no. 2, pp. 171–180, 2017. View at: Publisher Site | Google Scholar
  184. S. Laouafa, A. Ribon-Demars, F. Marcouiller et al., “Estradiol protects against cardiorespiratory dysfunctions and oxidative stress in intermittent hypoxia,” Sleep, vol. 40, no. 8, 2017. View at: Publisher Site | Google Scholar
  185. S. A. de Almeida, E. R. G. Claudio, V. Mengal et al., “Estrogen therapy worsens cardiac function and remodeling and reverses the effects of exercise training after myocardial infarction in ovariectomized female rats.,” Frontiers in Physiology, vol. 9, article 1242, 2018. View at: Publisher Site | Google Scholar
  186. R. J. Steagall, F. Yao, S. R. Shaikh, and A. A. Abdel-Rahman, “Estrogen receptor α activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats,” Life Sciences, vol. 182, pp. 41–49, 2017. View at: Publisher Site | Google Scholar
  187. E. Nozik-Grayck, C. Woods, J. M. Taylor et al., “Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension,” American Journal of Physiology Lung Cellular and Molecular Physiology, vol. 307, no. 11, pp. L868–L876, 2014. View at: Publisher Site | Google Scholar
  188. J. Yu, Y. Zhao, B. Li, L. Sun, and H. Huo, “17β-Estradiol regulates the expression of antioxidant enzymes in myocardial cells by increasing Nrf2 translocation,” Journal of Biochemical and Molecular Toxicology, vol. 26, no. 7, pp. 264–269, 2012. View at: Publisher Site | Google Scholar
  189. H. Priyanka, H. C. Krishnan, R. V. Singh, L. Hima, and S. ThyagaRajan, “Estrogen modulates in vitro T cell responses in a concentration- and receptor-dependent manner: effects on intracellular molecular targets and antioxidant enzymes,” Molecular Immunology, vol. 56, no. 4, pp. 328–339, 2013. View at: Publisher Site | Google Scholar
  190. C. Campos, K. R. Casali, D. Baraldi et al., “Efficacy of a low dose of estrogen on antioxidant defenses and heart rate variability,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 218749, 7 pages, 2014. View at: Publisher Site | Google Scholar
  191. X. Zhu, Z. Tang, B. Cong et al., “Estrogens increase cystathionine-γ-lyase expression and decrease inflammation and oxidative stress in the myocardium of ovariectomized rats,” Menopause, vol. 20, no. 10, pp. 1084–1091, 2013. View at: Publisher Site | Google Scholar
  192. A. Ribon-Demars, V. Pialoux, A. Boreau et al., “Protective roles of estradiol against vascular oxidative stress in ovariectomized female rats exposed to normoxia or intermittent hypoxia,” Acta Physiologica, vol. 225, no. 2, article e13159, 2019. View at: Publisher Site | Google Scholar
  193. M. R. Meyer and M. Barton, “GPER blockers as Nox downregulators: a new drug class to target chronic non- communicable diseases,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 176, pp. 82–87, 2018. View at: Publisher Site | Google Scholar
  194. O. Lekontseva, Y. Jiang, C. Schleppe, and S. T. Davidge, “Altered neuronal nitric oxide synthase in the aging vascular system: implications for estrogens therapy,” Endocrinology, vol. 153, no. 8, pp. 3940–3948, 2012. View at: Publisher Site | Google Scholar
  195. Pooja, M. Sharma, K. Singh et al., “Estrogen receptor (ESR1 and ESR2)-mediated activation of eNOS-NO-cGMP pathway facilitates high altitude acclimatization,” Nitric Oxide, vol. 102, pp. 12–20, 2020. View at: Publisher Site | Google Scholar

Copyright © 2021 Du Xiang et al. 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.

Related articles

No related content is available yet for this article.
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views1099
Downloads526
Citations

Related articles

No related content is available yet for this article.

Article of the Year Award: Outstanding research contributions of 2021, as selected by our Chief Editors. Read the winning articles.