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RECEPTORS AND SIGNALING PATHWAYS

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

¹Clarian Cardiovascular Surgery, Departments of ²Surgery and ³Cellular and Integrative Physiology, and ⁴Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 22 January 2009 ; accepted in final form 6 February 2009

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 β (ERβ). Therefore, we hypothesized that ERβ mediates estrogen-induced cardioprotection through PI3K/Akt and antiapoptotic signaling in females but not in males. Isolated male and female hearts from ERβ knockout (ERβKO) and wild-type (WT) mice (n = 5 mice/group) were subjected to 20-min ischemia followed by 60-min reperfusion (Langendorff). Ablation of ERβ 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 ERβKO 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 ERβKO of either sex following I/R. Furthermore, deficiency of ERβ increased myocardial JNK activation in females but increased ERK1/2 activity in males during acute I/R. We conclude that ERβ 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 ERβ-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.

ischemia-reperfusion; apoptotic signaling; cardioprotection