Estrogen receptor β mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia

Abstract

Females have a lower incidence of heart failure and improved survival after myocardial ischemia-reperfusion (I/R) compared with males. Although estrogen-suppressed cardiomyocyte apoptosis may be mediated through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, it is unclear whether this action is mediated via estrogen receptor beta (ERbeta). Therefore, we hypothesized that ERbeta mediates estrogen-induced cardioprotection through PI3K/Akt and antiapoptotic signaling in females but not in males. Isolated male and female hearts from ERbeta knockout (ERbetaKO) and wild-type (WT) mice (n = 5 mice/group) were subjected to 20-min ischemia followed by 60-min reperfusion (Langendorff). Ablation of ERbeta significantly decreased postischemic recovery of left ventricular developed pressure in female, but not male, hearts. Reduced activation of PI3K and Akt was noted in female ERbetaKO hearts, which was associated with increased expression of caspase-3 and -8, as well as decreased Bcl-2 levels compared with WT. However, myocardial STAT3, SOCS3 (suppressor of cytokine signaling 3), VEGF, and TNF receptors 1 and 2 levels did not change in ERbetaKO of either sex following I/R. Furthermore, deficiency of ERbeta increased myocardial JNK activation in females but increased ERK1/2 activity in males during acute I/R. We conclude that ERbeta mediates myocardial protection via upregulation of PI3K/Akt activation, decreased caspase-3 and -8, and increased Bcl-2 in female hearts following I/R. These findings provide evidence of ERbeta-mediated PI3K/Akt and antiapoptotic signaling in the myocardium and may lend insight into the mechanistic pathways behind the observed variation in clinical outcomes between males and females after myocardial infarction.

Gender differences in apoptotic signaling in heart failure due to volume overload

“…Since treatment of the ovariectomized rat with estrogen resulted in an increase in the basal level of caspase 3 protein, it can be suggested that caspase 3 protein level is dependent on functioning ovaries. In fact, Wang et al [43] have recently reported that myocardial protection following ischemia-reperfusion by upregulating the PI3K/ Akt pathway whereas decreased caspase 3 and 9 and increased Bcl-2 in female hearts is mediated through estrogen receptor, ERb. In summary, this is the first study to clearly identify gender differences in cardiomyocyte apoptosis and pro-and anti apoptotic factors in hearts subjected to volume overload.…”

Impact of simulated microgravity on microvascular endothelial cell apoptosis

“…The downregulation of Bcl-2 secondary to the activation of NF-jB might be mediated by the overexpression of p53 (Aoki et al 2001). A previous study reported the significant increase in the expression of p53 in microgravity-exposed cells (Wang et al 2009b). Therefore, we deduced that the activation of NF-jB probably induced HPMEC apoptosis through the suppression of Bcl-2 under simulated microgravity conditions.…”

Crucial Role of Phospholamban Phosphorylation and S-Nitrosylation in the Negative Lusitropism Induced by 17β-estradiol in the Male Rat Heart

“…The PI3K/Akt pathway is involved in the acute nongenomic actions of 17βE2 in various cells types [32], as well as in many responses elicited by this hormone at the level of cardiac myocytes [46]. Its implication in 17βE2 effects has been related especially to heart protection against ischemia [47]. Upregulation of PI3K/Akt by 17βE2 results in eNOS activation via a transcription-independent mechanism [48,49] which is mainly associated with ERα activation [32].…”