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Estrogen Receptors and Myocardial Infarction: History
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Subjects: Endocrinology & Metabolism
Contributor: Tadeu Montagnoli , Jaqueline Da Silva

Estrogen receptors (ER) mediate functions beyond their endocrine roles, as modulation of cardiovascular, renal, and immune systems through anti-inflammatory and anti-apoptotic effects, preventing necrosis of cardiomyocytes and endothelial cells, and attenuating cardiac hypertrophy. Estradiol (E2) prevents cardiac dysfunction, increases nitric oxide synthesis, and reduces the proliferation of vascular cells, yielding protective effects, regardless of gender. Such actions are mediated by ER (ER-alpha (ERα), ER-beta (ERβ), or G protein-coupled ER (GPER)) through genomic or non-genomic pathways, which regulate cardiovascular function and prevent tissue remodeling.

  • estrogen receptor
  • myocardial infarction
  • ischemia-reperfusion
  • cardiovascular disease
  • cardiac dysfunction

1. Introduction

Cardiovascular diseases (CVD) are the leading cause of death worldwide and still represent a crescent burden [1], as they accounted for nearly one-third of global deaths in 2016 and are expected to cause a further three million deaths by 2030, according to the World Health Organization. Myocardial infarction (MI) is a serious manifestation of coronary heart disease and represents a substantial global health problem, affecting more than seven million people in the world each year [2] and causing more than a third of deaths in developed nations annually [3]. Atherosclerotic cardiovascular disease is responsible for numerous cardiovascular events, including MI, and remains the leading cause of morbidity and mortality worldwide [4]. Moreover, ischemic heart disease stands as the most common isolated cause of death globally, and its frequency is increasing globally [5].

Although heart failure (HF) is the leading cause of death regardless of sex, women tend to develop HF later and have a better prognosis [6]. MI remains the most common cause of HF, despite notable advances in the treatment of coronary artery disease (CAD) and MI over the past two decades [7]. Thus, early treatment of HF induced by MI is an important clinical strategy for a better prognosis. Investigation on the cardiovascular role of estrogen receptors (ER) has recently evidenced them as potential pharmacological targets for cardioprotection, and their modulation is currently under study for the development of new therapeutic strategies for the treatment of CVD. Until now, three subtypes of ER are known, two of which are nuclear receptors, ER-alpha (ERα) and ER-beta (ERβ), and a third G protein-coupled ER (GPER). Over the years, their presence and actions have been demonstrated in different tissues and organs apart from the reproductive system, as well as the involvement of estrogen deficiency in pathological processes, such as immune cell activation, endothelial dysfunction, atherosclerosis, and as a risk factor for the development of CVD [8]. Activation of ER promotes genomic and non-genomic mechanisms, which result in anti-inflammatory and anti-apoptotic properties, in addition to cytoprotective effects on cardiac and endothelial cells and attenuate pathological cardiac hypertrophy [9]. For this reason, those receptors are now regarded as potential targets for the treatment of MI-induced HF.

2. Estrogen Receptors and Distribution in the Cardiovascular System

Classically, estrogen exerts its actions by activating ERα and ERβ, which are encoded by the ESR1 and ESR2 genes, respectively [10][11]. These receptors bind 17β-estradiol (E2) with similar affinity in their C-terminal ligand-binding domains, which share 60% sequence homology between subtypes and are responsible for receptor activation and dimerization. Transcriptional activity is guided by nearly identical DNA-binding domains and two additional activation function domains [11][12][13]. In 1996, the orphan G protein-coupled receptor GPR30 was first identified, and subsequent studies demonstrated its binding to E2 with high affinity, although less than nuclear ER, leading to its current designation as GPER [14].

All subtypes of ER have a wide distribution pattern in the body and control important physiological functions, including reproductive, cardiovascular, muscular, and in the central nervous system. Both ERα and ERβ are expressed in the cardiovascular system [15], particularly in cardiomyocytes, cardiac fibroblasts (CF), endothelium and epithelial cells in both male and female rats [16], as well as vascular smooth muscle cells (VSMC) of humans [16]. Despite their predominant cytoplasmic localization and genomic effects, ERα and ERβ can also promote rapid non-genomic cell signaling when embedded in the cell membrane. Detection of ERα and ERβ in mitochondria [16][17] and ERβ in adipose tissue and immune system [15] has also been reported.

Several studies identified GPER mRNA in the kidney and heart [18], including endothelial cells from cardiac and renal arterioles, and in smooth muscle cells [19]. GPER shows a broad distribution in the human heart, being expressed in both ventricles and atria, as well as in the atrioventricular sinus and aorta [20]. Moreover, in male mice ventricles, GPER mRNA is three- and seventeen-times more abundant than ESR1 and ESR2 mRNA, respectively [21]. It also displays a phenotype-dependent subcellular location, as its presence in endoplasmic reticulum membranes has been demonstrated [14] as well as in the plasma membrane. In cardiomyocytes, GPER is located in the cell membrane, cytoplasm [20][22] and mitochondria [22]. In addition, it is also found in VSMC cytoplasm and in the endoplasmic reticulum of endothelial cells [23].

Therefore, as the different ER subtypes show a wide distribution in most cell types of the cardiovascular system, their actions have been extensively investigated for the treatment of CVD, including MI, which will be further explored in the following sessions.

3. General Mechanism of Action of ER

Estrogen binding to ERα or ERβ in their monomeric form promotes homo- or hetero-dimerization, nuclear translocation, and association to co-regulators of gene transcription (canonical signaling) [24][25] and also may indirectly regulate gene expression by interactions with c-Jun and c-Fos [25], as demonstrated by the reduction in c-Jun-mediated gene transcription by E2 [26]. However, cell membrane ERα and ERβ [27] trigger rapid phosphorylation cascades through membrane-associated proteins. ERα enhances endothelial nitric oxide synthase (eNOS) activity in endothelial cells by stimulation of phosphatidylinositol 3-kinase (PI3K), while endothelial ERβ in caveolae also leads to NO production enhancement [10]. E2 promotes vasodilation by genomic pathways, increasing NOS3 transcription and exhibits anti-mitogenic effects in smooth muscle cells by inhibition of mitogen-activated protein kinase (MAPK) [28], whereas, in endothelial cells, it stimulates eNOS and vascular endothelial growth factor (VEGF), both involved with cell proliferation [9][28]. Moreover, ER activation of PI3K/Akt pathway also inhibits the pro-apoptotic effects of transcription factors belonging to the forkhead family (FKHR) while stimulates gene transcription of anti-apoptotic proteins through nuclear factor kappa B (NF-κB) [29]. ERβ activation of PI3K and protein kinase A (PKA) also blocks the development of cardiac hypertrophy and fibrosis [26][27].

Activation of GPER produces vasorelaxation through an increase in 3′,5′-cyclic adenosine monophosphate (cAMP) [23][30], caused by the release of endothelial nitric oxide (NO) [30][31] and the inhibition of the vasoconstrictor activity of endothelial-derived prostanoids [32]. GPER also inhibits endothelial cell and VSMC proliferation [33]. In VSMC, GPER seems to be involved in extracellular signal-regulated kinase (ERK) phosphorylation [34] and activation of c-Fos by either ERK or PI3K pathways [35]. The proliferation of rat CF is limited by GPER through suppressing cell cycle proteins cyclin B1 and cyclin-dependent kinase 1 (CDK1) [36]. GPER activation also demonstrates anti-inflammatory effects by downregulation of interleukin (IL)-6 expression in macrophages by repression of NF-κB activity, through modulation of inhibitor of κB kinases (IKK) and c-jun N-terminal kinase (JNK) phosphorylation [37].

In summary, canonical activation of ERα promotes gene transcription of anti-oxidant enzymes, such as superoxide dismutase 2 (SOD2), and downregulates inflammatory proteins, like tumor necrosis factor (TNF)-α. Similarly, ERβ induces upregulation of proteins involved in vascular tone control (eNOS and cyclooxygenase-2) and downregulates proinflammatory and profibrotic gene programs. Membrane ERα and ERβ enhances NO production through eNOS phosphorylation and RhoA-associated kinase (ROCK) inhibition, and membrane ERβ also increases protein S-nitrosylation (SNO) via eNOS. Furthermore, GPER also increases NO production by eNOS phosphorylation and increases ERK/glycogen synthase kinase (GSK)-3β pathway activation while reduces TNF-α production and cyclin B1 and CDK1 activity (Figure 1). Therefore, the activation of ER in the cardiovascular system could be expected to reduce cardiac remodeling and the progression of HF induced by MI.

Ijms 22 00525 g001 550

Figure 1. Representative scheme of the main pharmacological agents targeting ER and signaling pathways involved in the mechanism of action of their genomic and non-genomic effects. (Act., activation; Inh., inhibition; Phosph., phosphorylation. Underlined: ER subtype-selective agonists and antagonists).

4. ER Modulation and MI: Preclinical Studies

In OVX-MI mice, activation of ERα reduces mortality in spite of increasing infarction extension, while stimulation of ERβ accounts for reduced infarction area and increased cardiac hypertrophy and mortality [38]. These effects are blocked by fulvestrant, an antagonist of both ERα and ERβ [39], and GPER agonist [9][40]. E2 exerts protective effects through activation of bone marrow-derived endothelial progenitor cells (EPCs), which infiltrate the infarcted myocardium and promote angiogenesis in OVX-MI mice [41][42]. When in co-culture with cardiomyocytes from MI rats, incubation of c-kit+ cardiac cells with E2 or propylpyrazoletriol (PPT), a selective ERα receptor agonist, increases myocyte survival, while the selective ERβ agonist, 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN) is devoid of action [43]. Activation of both ER also regulates mitochondrial SOD2 expression in endothelial cells, with ERβ controlling basal gene expression and ERα mediating gene transcription under stress conditions, thus reducing ROS production [41]. In addition, ERβ mediates cardioprotection in I/R on OVX mice through the PI3K/Akt pathway and anti-apoptotic signaling [44] and diminishes post-MI fibrosis [26][45].

Estrogen depletion further accelerates the development of atherosclerosis, and treatment with G-1, a selective GPER agonist with similar affinity as E2, reduces atherosclerosis and inflammation with no uterotrophic effects [23]. The assumption that GPER is involved in cardioprotection via ERK was confirmed in a study using three different knockouts for ER (ESR1−/−, ESR2−/− e GPER−/−) in male mice. It showed that only GPER−/− hearts did not show E2-induced cardioprotection after I/R in relation to cardiac function, infarction size, and mitochondrial Ca2+ overload, suggesting that activation of MEK/ERK pathway via GSK-3β would be responsible for the beneficial effects [21]. It was shown that cardioprotection by E2 on I/R is blocked in mice of both sexes by G-15, a selective GPER antagonist, assuring the role of GPER activation [24]. Besides that, its activation with G-1 promotes the reduction of infarction size, myocardial fibrosis, and ventricular remodeling in OVX-MI females [46][47]. However, the improvement in cardiac remodeling in OVX-MI seems to involve both GPER and ERα, as the phosphorylation of Akt and eNOS observed after treatment with E2, G-1, or PPT is not totally blocked by G-15, fulvestrant, or actinomycin D [46].

Studies with selective ER modulators (SERM), such as tamoxifen, were also performed [48]. Long-term raloxifene treatment does not activate ERα, but activates GPER instead [39][49], reducing MI-induced arrhythmias and attenuating cardiac damage and apoptosis after I/R in OVX rats, which correlates to lower neutrophil infiltration and suppression of NF-κB activity [50].

Therefore, E2 displays a broad range of cardioprotective effects and can be useful for the treatment of CVD, especially MI. Besides anti-dyslipidemic, anti-atherogenic, and vasodilator effects, E2 may exert direct cardiac effects, such as increasing cell survival, stimulating ischemic preconditioning, regulating myocardial hypertrophy and fibrosis, as well as normalizing cardiac function and rhythm. Then, ERα stimulates myocardial regeneration and angiogenesis through activation of c-kit+ cardiac cells and EPC and improves antioxidant mechanisms and cardiac function while reduces VSMC calcification, coronary tonus, fibrosis, and post-MI mortality. In general, ERβ stimulation leads to upregulation of antioxidant and anti-apoptotic gene programs, although its role in attenuating fibrosis and arrhythmias has already been shown. Besides, GPER activation generates not only coronary vasodilation and controls cholesterol catabolism and inflammation but also improves cardiac conditioning after I/R injury. Moreover, ERα and GPER synergistically contribute to reduction in infarct size and ventricular remodeling, and these beneficial actions prompt further research on estrogen effects in MI patients.

5. Genetic Factors Related to Estrogen Receptors and MI

Estrogen and related HRT activate ER, which in turn regulate gene transcription of proteins associated with CVD risk factors. Individuals with variations in ESR1 are more susceptible to cardiovascular complications, including ischemic heart disease and MI. In a prospective study including 1739 participants, 49.7% women, two ESR1 polymorphisms were detected (ESR1 c.454-397>C and ESR1 c.454-351>G), and it was suggested that recessive individuals for the C allele (nearly 20% of the cohort population) were more likely (at a two-fold rate) to develop CVD including MI [51]. More recently, it was reported that men bearing the genotype ESR1 c.454-397CC could also be at risk for stroke [52]. In a population-based prospective cohort study involving 6408 participants, 59.2% women, polymorphisms c.454-397T>C and c.454-351A>G were observed in the ESR1, with the possibility of four haplotype alleles and during a seven-year follow-up, 285 patients had MI and 440 had ischemic heart disease. These studies found that only postmenopausal women who carry ESR1 haplotype 1 (c.454-397T and c.454-351A alleles) had an increased risk of MI and ischemic heart disease, regardless of known cardiovascular risk factors, while no correlation was observed for men [53]. Women with a variant phenotype CC of ESR1 (c.454-397T>C) also had thicker coronary intima compared to women with TT genotype, pointing to the importance of ESR1 genotype in susceptibility to CVD [54]. The -351A/G ESR1 polymorphism may be associated with MI, but not with extreme longevity, as the AA genotype (-351A/G) is more frequent in women with MI than in aged women with no history of MI or young patients. Moreover, in MI patients, the GG genotype (-351A/G) was associated with more favorable levels of total cholesterol, LDL-C, and HDL-C compared to the AG and AA genotype [55].

Considering the ESR2 gene, single nucleotide polymorphisms could affect the susceptibility to MI in a sex-dependent manner. The rs1271572T allele was significantly more common in patients who developed MI being more pronounced in men, as well the T variant was associated with an increased risk of MI in the Spanish population and was considered limited to men only [56]. Another variant of the ESR2 gene, G1730A, was also related to a higher incidence of MI in younger men, while no correlation was found between this variant and the occurrence of MI in women [57]. ESR2 polymorphisms may also be associated with an increased risk of metabolic syndrome in postmenopausal women [58] and contribute to salt-sensitive blood pressure in premenopausal women [59].

Given their most recent discovery relative to ERα and ERβ, CVD-related GPER polymorphisms have not been thoroughly investigated although associations were already demonstrated to idiopathic scoliosis [60], the risk for seminoma [61] and uterine leiomyoma [62] and more recently, with risk and development of hypertension [63]. Moreover, a hypofunctional GPER variant P16L has recently been identified and associated with increased LDL-C in plasma, which may pose an additional risk of atherosclerosis [64].

ER gene variations are important factors associated with a risk for CVD in a sex-dependent manner and may possibly determine pharmacological responses for ER-targeted therapies. While ERS1 variations in women show correlations with increased risk for CVD, including MI, ERS2 polymorphisms may increase MI susceptibility in men. However, ER gene variants may also predispose to increased risk factors for CVD, as seen in women bearing ERS2 variants or a hypo-functional GPER variant.

5. Conclusion

In fact, it is undeniable that ER modulation causes a wide range of effects on the cardiovascular system, the activation of “classic” ER and GPER demonstrate beneficial properties that could be explored for the treatment of MI and consequent prevention of HF. Further research should address questions such as the elucidation of molecular mechanisms underlying cardiovascular estrogen actions, as well as the influence of clinical features like age, menopause onset, genetic background, and presence of risk factors on the beneficial cardiovascular effects observed during estrogen therapy and ER activation.

This entry is adapted from the peer-reviewed paper 10.3390/ijms22020525

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