The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

Abstract

Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.

Keywords: Angiogenesis; Cardiovascular disease; Estrogen; Estrogen receptor alpha; Estrogen receptor beta; Fibrosis; GPR30; Hormone replacement therapy; Oxidative stress; Vasodilation.

Fig. 1

Genomic and non-genomic actions of E2. E2 can regulate gene expression and activity of signaling molecules by binding to ERs via genomic and/or non-genomic pathways. In genomic regulation, binding of E2 to the ER promotes the formation of homo/hetero dimers, translocation to the nucleus and direct binding to estrogen response elements (ERE), or to transcription factors which regulate transcription of its target genes including VEGF, a pro-angiogenic factor. In non-genomic regulation, binding of E2 to ERs and GPR30 at the plasma membrane leads to activation of MAPK/ERK/PI3K/cAMP, which induce gene expression including eNOS, a potent vasodilator. E2 also binds to ERs localized on the mitochondrial membrane improving mitochondrial function by decreasing ROS production and increasing cell survival. Local E2 biosynthesis from the conversion of T to E2 via aromatase (CYP450) is also shown. Genomic pathways are shown in red arrows, whereas non-genomic pathways are shown in blue arrows. Abbreviations: E2 estrogen, ER estrogen receptor, ERE estrogen response element, T testosterone, GPCR G-protein-coupled receptor, PI3K phosphoinositide 3-kinase, MAPK mitogen activated protein kinase, AKT protein kinase B, VEGF vascular endothelial growth factor

Fig. 2

Summary of the likely protective mechanisms of estrogen against cardiovascular disease. Illustration of the possible beneficial effects of estrogen for the treatment of cardiovascular diseases such as ischemic heart disease and heart failure. The protective effect of estrogen in cardiovascular disease is associated with reduced fibrosis, stimulation of angiogenesis, and vasodilation, improved mitochondrial function, and reduced oxidative stress. Abbreviations: VEGF vascular endothelial growth factor, eNOS endothelial nitric oxide synthase, AngII angiotensin II, MMP2 matrix metalloproteinase 2, ROS reactive oxygen species, FAO fatty acid oxidation