Cardiomyocyte-specific Estrogen Receptor Alpha Increases Angiogenesis,Lymphangiogenesis and Reduces Fibrosis in the Female Mouse Heart Post-Myocardial Infarction

Abstract

Experimental studies showed that 17β-estradiol (E2) and activated Estrogen Receptors (ER) protect the heart from ischemic injury. However, the underlying molecular mechanisms are not well understood. To investigate the role of ER-alpha (ERα) in cardiomyocytes in the setting of myocardial ischemia, we generated transgenic mice with cardiomyocyte-specific overexpression of ERα (ERα-OE) and subjected them to Myocardial Infarction (MI). At the basal level, female and male ERα-OE mice showed increased Left Ventricular (LV) mass, LV volume and cardiomyocyte length. Two weeks after MI, LV volume was significantly increased and LV wall thickness decreased in female and male WT-mice and male ERα-OE, but not in female ERα-OE mice. ERα-OE enhanced expression of angiogenesis and lymphangiogenesis markers (Vegf, Lyve-1), and neovascularization in the peri-infarct area in both sexes. However, attenuated level of fibrosis and higher phosphorylation of JNK signaling pathway could be detected only in female ERα-OE after MI. In conclusion, our study indicates that ERα protects female mouse cardiomyocytes from the sequelae of ischemia through induction of neovascularization in a paracrine fashion and impaired fibrosis, which together may contribute to the attenuation of cardiac remodelling.

Endothelin-1 upregulation mediates aging-related cardiac fibrosis

“…In this study, we observed ER-α expression to be significantly lower in senescent P30 fibroblasts and in the aged mice hearts than in corresponding P3 fibroblasts and young mice hearts, which suggest that the relationship between ER-α and ET-1 may be strategically important to aging-related cardiac fibrosis. A recent study indicated that ER-α expression in the female mouse hearts reduces cardiac fibrosis following myocardial ischemia [31]. The precise role of ER-α down-regulation in fibrosis in the aged hearts and in aging related cardiac dysfunction cannot be discerned from the present work.…”

Sex and Gender Differences in Ischemic Heart Disease: Endocrine Vascular Disease Approach (EVA) Study Design

“…Indeed, the estrogen receptor (ER) beta versus ER-alpha receptor-mediated responses and the relative importance of genomic versus non-genomic effects are the subjects of considerable debate [43,47]. The cardioprotective role of E2 in the modulation of ischemia-reperfusion injury has been extensively investigated: in models, E2 acts at multiple cellular levels during ischemia-reperfusion, including cardiomyocytes and fibroblasts [46,[48][49][50][51].…”

The protective role of p72 in doxorubicin-induced cardiomyocytes injury in vitro

“…Estrogen receptors are suggested to be important in various pathophysiologies, including cardiac dysfunctions (17,18). In clinic practice, estrogen treatment markedly improves myocardiac infarct size and heart failure (19). Previous studies have determined that ERs activate the downstream PI3K/Akt signaling pathway, thereby limiting the inflammatory responses in vivo and in vitro (19,20).…”

“…In clinic practice, estrogen treatment markedly improves myocardiac infarct size and heart failure (19). Previous studies have determined that ERs activate the downstream PI3K/Akt signaling pathway, thereby limiting the inflammatory responses in vivo and in vitro (19,20). As an RNA helicase, p72 binds to double and single stranded RNA.…”