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

Meijing Wang, Yue Wang, Brent Weil, Aaron Abarbanell, Jeremy Herrmann, Jiangning Tan, Megan Kelly, Daniel R. Meldrum

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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 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume296
Issue number4
DOIs
StatePublished - Apr 2009

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Phosphatidylinositol 3-Kinase
Estrogen Receptors
Ischemia
Caspase 8
Caspase 3
Estrogens
Proto-Oncogene Proteins c-akt
Myocardial Reperfusion
Vascular Endothelial Growth Factor Receptor
Tumor Necrosis Factor Receptors
Ventricular Pressure
Cardiac Myocytes
Knockout Mice
Reperfusion
Myocardial Ischemia
Myocardium
Up-Regulation
Heart Failure
Myocardial Infarction
Apoptosis

Keywords

  • Apoptotic signaling
  • Cardioprotection
  • Ischemia-reperfusion

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Estrogen receptor β mediates increased activation of PI3K/Akt signaling and improved myocardial function in female hearts following acute ischemia. / Wang, Meijing; Wang, Yue; Weil, Brent; Abarbanell, Aaron; Herrmann, Jeremy; Tan, Jiangning; Kelly, Megan; Meldrum, Daniel R.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 296, No. 4, 04.2009.

Research output: Contribution to journalArticle

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