| First Author | Luo T | Year | 2016 |
| Journal | PLoS One | Volume | 11 |
| Issue | 12 | Pages | e0167761 |
| PubMed ID | 27930699 | Mgi Jnum | J:255201 |
| Mgi Id | MGI:6100063 | Doi | 10.1371/journal.pone.0167761 |
| Citation | Luo T, et al. (2016) Estrogen Protects the Female Heart from Ischemia/Reperfusion Injury through Manganese Superoxide Dismutase Phosphorylation by Mitochondrial p38beta at Threonine 79 and Serine 106. PLoS One 11(12):e0167761 |
| abstractText | 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 17beta-estradiol (E2) protects cultured neonatal rat cardiomyocytes from hypoxia/reoxygenation (H/R) by identifying a functionally active mitochondrial pool of p38beta and E2-driven upregulation of manganese superoxide dismutase (MnSOD) activity via p38beta, 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 p38beta and MnSOD. I/R-induced infarct size in ERalpha knockout (ERKO), ERbeta knockout (BERKO) and ERalpha and beta 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 ERalpha and ERbeta led to reduced activity of mitochondrial p38beta and MnSOD at baseline and after I/R. The physical interaction between mitochondrial p38beta 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 p38beta 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 p38beta. |
