17β-Estradiol Reduces Cardiomyocyte Apoptosis In Vivo and In Vitro via Activation of Phospho-Inositide-3 Kinase/Akt Signaling

Abstract

Abstract-Female gender and estrogen-replacement therapy in postmenopausal women are associated with improved heart failure survival, and physiological replacement of 17␤-estradiol (E2) reduces infarct size and cardiomyocyte apoptosis in animal models of myocardial infarction (MI). Here, we characterize the molecular mechanisms of E2 effects on cardiomyocyte survival in vivo and in vitro. Ovariectomized female mice were treated with placebo or physiological E2 replacement, followed by coronary artery ligation (placebo-MI or E2-MI) or sham operation (sham) and hearts were harvested 6, 24, and 72 hours later. After MI, E2 replacement significantly increased activation of the prosurvival kinase, Akt, and decreased cardiomyocyte apoptosis assessed by terminal deoxynucleotidyltransferase dUTP nick-end labeling (TUNEL) staining and caspase 3 activation. In vitro, E2 at 1 or 10 nmol/L caused a rapid 2.7-fold increase in Akt phosphorylation and a decrease in apoptosis as measured by TUNEL staining, caspase 3 activation, and DNA laddering in cultured neonatal rat cardiomyocytes. The E2-mediated reduction in apoptosis was reversed by an estrogen receptor (ER) antagonist, ICI 182,780, and by phospho-inositide-3 kinase inhibitors, LY294002 and Wortmannin. Overexpression of a dominant negative-Akt construct also blocked E2-mediated reduction in cardiomyocyte apoptosis. These data show that E2 reduces cardiomyocyte apoptosis in vivo and in vitro by ER-and phospho-inositide-3 kinase-Aktdependent pathways and support the relevance of these pathways in the observed estrogen-mediated reduction in myocardial injury. Key Words: estrogen Ⅲ estrogen receptors Ⅲ myocardial infarction Ⅲ cardiomyocyte Ⅲ apoptosis Ⅲ Akt Ⅲ PI3 kinase H eart failure is a growing public health problem, 1 with several studies demonstrating that women with heart failure have a better prognosis than men. 2,3,4,5,6,7 Whether endogenous sex hormones contribute to these differences in prognosis remains unknown. However, observational studies have demonstrated that postmenopausal women taking estrogen after a myocardial infarction (MI) have a lower incidence of heart failure. 8,9 Furthermore, retrospective analyses of multicenter heart failure trials have shown that postmenopausal women taking estrogen have a better prognosis than women not on estrogen, 10,11 supporting that estrogen may improve heart failure prognosis.Several studies have demonstrated increased cardiomyocyte apoptosis in failing hearts, 12,13 and further evidence suggests that apoptosis contributes to heart failure progression. 14,15 Moreover, autopsy studies have shown that female gender is associated with less cardiomyocyte apoptosis in normal and failing hearts compared with males. 16,17,18,19 These observed gender differences in cardiomyocyte survival provide a plausible explanation for the beneficial effect of female gender on heart failure progression.We recently showed that physiological estrogen replacement in ovariectomized female mice reduces infarct size both early and late after left c...

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

“…Phosphorylation of Akt at both Ser 473 and Thr 308 is necessary for this process (Shao, J. et al 2000). Beneficial effects of E 2 on PI3K/Akt signalling pathway and thus glucose transporters have been previously reported (Patten et al 2004, Tepavcevic et al 2011, Obradovic et al 2015a, Obradovic et al 2015b. This is consistent with our observation that following treatement with E 2 to HF fed rats there is an increase in the ratio of pAkt(Thr 308 )/Akt accompanying increased translocation of GLUT4 to the PM.…”

Phosphoinositide 3-kinases as a common platform for multi-hormone signaling

“…The activation of NOS indeed reduces inflammatory reactions and protects from the effects of ischemia/reperfusion (Simoncini et al 2000). Similarly, in an animal model of myocardial infarction, involving permanent coronary occlusion, E2-mediated activation of PI3K and PKB/Akt protects the heart by reducing both infarct size and myocyte apoptosis (Patten et al 2004). Overall, the activation of the ER/PI3K/Akt/eNOS pathway thus explains, in cultured human endothelial cells as well as in vivo, in intact elastic and muscular arteries, the molecular mechanism underlying the long-known protective effects of estrogen on female cardiovascular system (Haynes et al 2000, Guo et al 2005.…”

Epidemiology and pathophysiology of Takotsubo syndrome

“…It is well established that oestrogens reduced the inotropic and chronotropic responses to catecholamines, alter vascular reactivity and are cardioprotective [86][87][88] . Several studies demonstrate that myocardial βAR-mediated positive inotropic responses are greater in male hearts than matched female hearts, and these differences are mediated by a lower level of β1AR-signalling.…”