Prenatal hypoxia causes a sex-dependent increase in heart susceptibility to ischemia and reperfusion injury in adult male offspring: role of protein kinase C epsilon.

The present study tested the hypothesis that protein kinase C (PKC) epsilon plays a key role in the sex dichotomy of heart susceptibility to ischemia and reperfusion injury in adult offspring resulting from prenatal hypoxic exposure. Time-dated pregnant rats were divided between normoxic and hypoxic (10.5% O(2) on days 15-21 of gestation) groups. Hearts of 3-month-old progeny were subjected to ischemia and reperfusion (I/R) injury in a Langendorff preparation. Preischemic values of left ventricle (LV) function were the same between control and hypoxic animals. Prenatal hypoxia significantly decreased postischemic recovery of LV function and increased cardiac enzyme release and infarct size in adult male, but not female, rats. This was associated with significant decreases in PKC(epsilon) and phospho-PKC(epsilon) levels in the LV of the male, but not female, rats. The PKC(epsilon) translocation inhibitor peptide (PKC(epsilon)-TIP) significantly decreased phospho-PKC(epsilon) in control male rats to the levels found in the hypoxic animals and abolished the difference in I/R injury observed between the control and hypoxic rats. In females, PKC(epsilon)-TIP inhibited PKC(epsilon) phosphorylation and decreased postischemic recovery of LV function equally well in both control and hypoxic animals. PKC(epsilon)-TIP had no effect on PKCdelta activation in either male or female hearts. The results demonstrated that prenatal hypoxia caused an increase in heart susceptibility to ischemia and reperfusion injury in offspring in a sex-dependent manner, which was due to fetal programming of PKC(epsilon) gene repression resulting in a down-regulation of PKC(epsilon) function in the heart of adult male offspring.