Sex-Gender Disparities in Cardiovascular Diseases: The Effects of Estrogen on eNOS, Lipid Profile, and NFATs During Catecholamine Stress

Abstract

Cardiovascular diseases (CVDs) characterized by sex-gender differences remain a leading cause of death globally. Hence, it is imperative to understand the underlying mechanisms of CVDs pathogenesis and the possible factors influencing the sex-gender disparities in clinical demographics. Attempts to elucidate the underlying mechanisms over the recent decades have suggested the mechanistic roles of estrogen in modulating cardioprotective and immunoregulatory effect as a factor for the observed differences in the incidence of CVDs among premenopausal and post-menopausal women and men. This review from a pathomechanical perspective aims at illustrating the roles of estrogen (E2) in the modulation of stimuli signaling in the heart during chronic catecholamine stress (CCS). The probable mechanism employed by E2 to decrease the incidence of hypertension, coronary heart disease, and pathological cardiac hypertrophy in premenopausal women are discussed. Initially, signaling via estrogen receptors and β-adrenergic receptors (βARs) during physiological state and CCS were summarized. By reconciling the impact of estrogen deficiency and hyperstimulation of βARs, the discussions were centered on their implications in disruption of nitric oxide synthesis, dysregulation of lipid profiles, and upregulation of nuclear factor of activated T cells, which induces the aforementioned CVDs, respectively. Finally, updates on E2 therapies for maintaining cardiac health during menopause and suggestions for the advancement treatments were highlighted.

Keywords: NFATs; cardiovascular diseases; catecholamine stress; eNOS; estrogen; lipid profile; β-adrenergic receptors.

Figure 1

Schematic illustration of estrogen receptors (ERs) and β-adrenergic receptors (βARs) signaling. AC, Adenylyl cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; GRKs, G-protein-coupled receptor kinases; E2, estrogen; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PDE, phosphodiesterase; PLB, phospholamban; LTCC, L-type calcium channel; CaMK, calmodulin-dependent kinase; ERE, estrogen receptor element; Sp-1, stimulating protein-1; NFAT, nuclear factor of activated T cells; , Phosphorylated; , Inhibit; , Upregulate; , Catecholamine.

Figure 2

Graphical abstract of sex–gender disparities in cardiovascular diseases mediated by the mechanistic role of estrogen on eNOS, lipid profile, and NFATs. eNOS, endothelial nitric oxide synthase; NO, nitric oxide; Ang II, angiotensin II; AT2R, angiotensin II receptor type 2; MasR, Mas receptor; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; RMT, receptor-mediated transcytosis; SR-B1, scavenger receptor class B type 1; PCSK9, proprotein convertase subtilisin/kexin type 9; GRK5, G protein-coupled receptor kinases 5; HDAC, histone deacetylase; , signaling; , upregulate; , downregulate; , inhibit; , normalize.