Abstract
A collective body of evidence indicates that estrogen protects the heart from myocardial ischemia/reperfusion (I/R) injury, but the underlying mechanism remains incompletely understood. We have previously delineated a novel mechanism of how 17β-estradiol (E2) protects cultured neonatal rat cardiomyocytes from hypoxia/reoxygenation (H/R) by identifying a functionally active mitochondrial pool of p38β and E2-driven upregulation of manganese superoxide dismutase (MnSOD) activity via p38β, leading to the suppression of reactive oxygen species (ROS) and apoptosis. Here we investigate these cytoprotective actions of E2 in vivo. Left coronary artery ligation and reperfusion was used to produce I/R injury in ovariectomized (OVX) female mice and in estrogen receptor (ER) null female mice. E2 treatment in OVX mice reduced the left ventricular infarct size accompanied by increased activity of mitochondrial p38β and MnSOD. I/R-induced infarct size in ERα knockout (ERKO), ERβ knockout (BERKO) and ERα and β double knockout (DERKO) female mice was larger than that in wild type (WT) mice, with little difference among ERKO, BERKO, and DERKO. Loss of both ERα and ERβ led to reduced activity of mitochondrial p38β and MnSOD at baseline and after I/R. The physical interaction between mitochondrial p38β and MnSOD in the heart was detected by co-immunoprecipitation (co-IP). Threonine 79 (T79) and serine 106 (S106) of MnSOD were identified to be phosphorylated by p38β in kinase assays. Overexpression of WT MnSOD in cardiomyocytes reduced ROS generation during H/R, while point mutation of T79 and S106 of MnSOD to alanine abolished its antioxidative function. We conclude that the protective effects of E2 and ER against cardiac I/R injury involve the regulation of MnSOD via posttranslational modification of the dismutase by p38β.
Highlights
The incidence of cardiovascular diseases (CVD) is significantly lower in women than in agematched men until menopause, after which CVD risk accelerates to equal or exceed that in men
In our previous work, we showed that 17β-estradiol (E2) inhibited reactive oxygen species (ROS) generation in vitro in a simulated I/R in the form of hypoxia/reoxygenation (H/R) applied to cultured neonatal rat cardiomyocytes (NRCM) [15, 16]
This is consistent with prior observations made from an in-vitro H/R model in NRCM that E2 does not alter manganese superoxide dismutase (MnSOD) protein expression, while the hormone significantly augments the enzymatic activity [17]
Summary
The incidence of cardiovascular diseases (CVD) is significantly lower in women than in agematched men until menopause, after which CVD risk accelerates to equal or exceed that in men. The hormone’s antioxidative effect may play a significant role in protecting cardiomyocytes against I/R injury, though the detailed mechanism of how estrogen suppresses oxidative stress is not fully understood. In our previous work, we showed that 17β-estradiol (E2) inhibited ROS generation in vitro in a simulated I/R in the form of hypoxia/reoxygenation (H/R) applied to cultured neonatal rat cardiomyocytes (NRCM) [15, 16]. This protection was dependent on both estrogen receptor alpha (ERα) and beta (ERβ). The suppression of mitochondrial ROS production was associated with upregulating the activity of p38β and prevented cardiomyocyte apoptosis. We further delineated the mechanism by which E2-induced p38β regulates redox by demonstrating a pool of functionally active mitochondrial p38β and the kinase-substrate relationship between p38β and manganese superoxide dismutase (MnSOD) [17]
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