Gender differences in cardioprotection against ischemia/reperfusion injury in adult rat hearts: Focus on akt and protein kinase C signaling

Abstract

Previous studies have reported the sex differences in heart susceptibility to ischemia/reperfusion (I/R) injury, but the mechanisms are not understood. The present study tested the hypothesis that Akt and protein kinase C (PKC)ε play an important role in the sexual dimorphism of heart susceptibility to I/R injury. Isolated hearts from 2-month-old male and female rats were subjected to I/R in the Langendorff preparation. The postischemic recovery of left ventricular function was significantly better, and infarct size was significantly smaller in female (37.1 ± 1.9%) than in male (48.3 ± 2.3%) hearts after 25-min ischemia followed by 2-h reperfusion. Inhibition of phosphatidylinositol 3-kinase/Akt pathway by wortmannin or PKC by chelerythrine chloride before ischemia significantly reduced postischemic recovery and increased infarct size in female but not male hearts. There were no differences in myocardial protein levels of heat shock protein 70, Akt, and PKCε, respectively, between male and female rats. However, the ratio of phosphorylated (p)-Akt/Akt (0.58 ± 0.05 versus 0.22 ± 0.04; P < 0.05) and p-PKCε/PKCε (0.35 ± 0.03 versus 0.22 ± 0.02; P < 0.05) was significantly higher in female than in male hearts. In addition, there were significant increases in p-Akt and p-PKCε levels during reperfusion in female but not in male hearts. The results suggest that increased p-Akt and p-PKCε levels in female hearts contribute to the gender-related differences in heart susceptibility to I/R and play an important role in cardioprotection against I/R injury in females. Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics.