Abstract
Numerous epidemiological, clinical, and animal studies showed that cardiac function and manifestation of cardiovascular diseases (CVDs) are different between males and females. The underlying reasons for these sex differences are definitely multifactorial, but major evidence points to a causal role of the sex steroid hormone 17β-estradiol (E2) and its receptors (ER) in the physiology and pathophysiology of the heart. Interestingly, it has been shown that cardiac calcium (Ca2+) ion channels and mitochondrial function are regulated in a sex-specific manner. Accurate mitochondrial function and Ca2+ signaling are of utmost importance for adequate heart function and crucial to maintaining the cardiovascular health. Due to the highly sensitive nature of these processes in the heart, this review article highlights the current knowledge regarding sex dimorphisms in the heart implicating the importance of E2 and ERs in the regulation of cardiac mitochondrial function and Ca2+ ion channels, thus the contractility. In particular, we provide an overview of in-vitro and in-vivo studies using either E2 deficiency; ER deficiency or selective ER activation, which suggest that E2 and ERs are strongly involved in these processes. In this context, this review also discusses the divergent E2-responses resulting from the activation of different ER subtypes in these processes. Detailed understanding of the E2 and ER-mediated molecular and cellular mechanisms in the heart under physiological and pathological conditions may help to design more specifically targeted drugs for the management of CVDs in men and women.
Highlights
Cardiovascular Diseases (CVDs) are one of the top age-associated chronic diseases with growing importance due to the dramatic increase in life expectancy [1] and are the leading cause of mortality in men and women worldwide [2]
Calcium (Ca2+) is a key player in the regulation of myocardial contraction and the deregulation of Ca2+ signaling due to the alteration of Ca2+ ion channels function in cardiomyocytes is highly associated with the development of cardiac diseases, such as heart failure [4]
In a mouse model of exercise-induced physiological myocardial hypotrophy, we demonstrated that only female wild type (WT)-mice showed an increase in the expression of key regulators of mitochondrial function e.g., NRF-1,−2, Mef2a, Atp5k, and electron transport chain proteins after running
Summary
Cardiovascular Diseases (CVDs) are one of the top age-associated chronic diseases with growing importance due to the dramatic increase in life expectancy [1] and are the leading cause of mortality in men and women worldwide [2]. In the vast majority of CVDs, there are well described sex differences in the incidence, pathophysiology, and outcomes of diseases [3]. As result of these observations, research over the last few decades has focused on the contribution of sex steroid hormones, 17β-estradiol (E2), on the cardiovascular system and mechanistic pathways in the diseased heart
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