Abstract
The present study tested the hypothesis that protein kinase C (PKC) ϵ 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% O2 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 PKCϵ and phospho-PKCϵ levels in the LV of the male, but not female, rats. The PKCϵ translocation inhibitor peptide (PKCϵ-TIP) significantly decreased phospho-PKCϵ 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, PKCϵ-TIP inhibited PKCϵ phosphorylation and decreased postischemic recovery of LV function equally well in both control and hypoxic animals. PKCϵ-TIP had no effect on PKCδ 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 PKCϵ gene repression resulting in a down-regulation of PKCϵ function in the heart of adult male offspring.
Footnotes
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This work was supported in part by the National Institutes of Health [Grants HL83966, HL82779].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.153239.
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ABBREVIATIONS: PKC, protein kinase C; LV, left ventricle; dP/dtmax, maximal rate of contraction; dP/dtmin, maximal rate of relaxation; LVEDP, left ventricle end diastolic pressure; TIP, translocation inhibitor peptide; LVDP, left ventricle developed pressure; HR, heart rate; LDH, lactate dehydrogenase; RACK, receptors for activated C-kinase.
- Received March 6, 2009.
- Accepted May 22, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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