The long-term goal of the project is to study the effect of prenatal hypoxia on fetal heart development and its lifelong pathophysiological consequences in the adult heart. Of all the stresses to which the fetus is subjected, perhaps the most important and clinically relevant is that of hypoxia. Human epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of ischemic heart disease in adulthood. Recently, we have found that prenatal hypoxia increases apoptosis in the fetal heart and causes a gender-dependent increase in heart susceptibility to ischemia and reperfusion injury in adult male offspring. Among other mechanisms, numerous studies have demonstrated that PKCe plays a pivotal role of cardioprotection during ischemia and reperfusion injury. Our preliminary data showed that prenatal hypoxia decreased PKCe protein levels selectively in the heart of adult male offspring, suggesting an in utero, gender-specific programming of PKCe gene expression pattern in the heart. The proposed studies focus on the underlying mechanisms, and will test the main hypothesis that prenatal hypoxia causes a gender-specific increase in DMA methylation of the PKCe gene and a down-regulation of PKCe gene expression in the heart, resulting in an increased heart susceptibility to ischemia and reperfusion injury in adult male offspring. To test the hypothesis, 4 Specific Aims are designed, which will test whether prenatal hypoxia causes 1) a gender- specific increase in heart susceptibility to ischemia and reperfusion injury in adult offspring, 2) a gender-specific down-regulation of PKCe gene expression in the heart, 3) a gender-specific increase in DNA methylation of the PKCe gene in the heart, and 4) whether DNA methylation of the PKCe gene plays a key role in the prenatal hypoxic-induced, gender-specific increase in heart susceptibility to ischemia and reperfusion injury. To achieve these aims, we propose a series of experiments in a pregnant rat model, and will determine the effects of prenatal hypoxic exposure on DNA methylation of the PKCe gene, PKCe gene expression, and postischemic recovery of left ventricular function and myocardial infarct size in hearts of male and female fetuses, and male and female adult offspring. The results will provide exciting novel insights into molecular mechanisms of epigenetic programming in the gene expression pattern involved in the adverse effects of fetal chronic hypoxia on the heart development, and its lifelong pathophysiological consequences in the adult heart. ? ? ?
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