Estrogen Receptors: Therapeutic Perspectives for the Treatment of Cardiac Dysfunction after Myocardial Infarction.

Jaqueline S Da Silva,Bruna S Rocha,Sophia C P Marinho,Gisele Zapata-Sudo,Tadeu L Montagnoli,Matheus L C A Tacco

doi:10.3390/ijms22020525

Abstract

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. Despite the extensive knowledge on the cardioprotective effects of estrogen, clinical studies conducted on myocardial infarction (MI) and cardiovascular diseases still include favorable and unfavorable profiles. The purpose of this review is to provide up-to-date information regarding molecular, preclinical, and clinical aspects of cardiovascular E2 effects and ER modulation as a potential therapeutic target for the treatment of MI-induced cardiac dysfunction.

Highlights

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
The improvement in cardiac remodeling in OVX-Myocardial infarction (MI) seems to involve both G protein-coupled ER (GPER) and ERα, as the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) observed after treatment with E2, G-1, or PPT is not totally blocked by G-15, fulvestrant, or actinomycin D [58]. These results indicate mechanisms relying on both GPER and membrane ERα, which converge to activation of phosphatidylinositol 3-kinase (PI3K)/Akt/eNOS
A meta-analysis including 23 controlled and randomized clinical studies indicated that women under 60 years old or ten years of menopause onset experience a 32% reduction in coronary artery disease (CAD) incidence by hormone replacement therapy (HRT), while women of older age or over ten years of menopause onset do not benefit from this treatment

Summary

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. 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 regarded as potential targets for the treatment of MI-induced HF

Estrogen Receptors and Distribution in the Cardiovascular System

General Mechanism of Action of ER

ER Modulation and MI

Genetic Factors Related to Estrogen Receptors and MI

Findings

Conclusions