Epidemiological studies indicate beneficial effects of moderate alcohol consumption on heart , in particular in regard to coronary heart disease. Although most of the studies focused on the effect of moderate consumption on atherosclerosis, evidence suggesting direct beneficial effect on the muscle resistance to post-ischemic reperfusion injury has also been obtained. The molecular mechanisms that account for the direct effect on the muscle are not understood. Protein kinase C (PKC)-mediated signal transduction system has been found to be affected by ethanol. Because this signal transduction system regulates protection of the heart from ischemia and post-ischemic reperfusion injury, ethanol-induced changes in components of this signaling system may account for at least some of the beneficiary effects of moderate alcohol consumption. The investigators used isolated adult cardiac myocytes and isolated intact heart to demonstrate that exposure to ethanol activates specific PKC isozymes and thus provides protection from prolonged hypoxia or ischemia. They also showed similar protection in guinea pigs fed ethanol for prolonged period, in vivo. The investigators plan to continue and expand this research. Specifically:
AIM A. Using an isolated adult rat cardiomyocyte, they will determine the cardioprotection induced by a short exposure to ethanol and the role of PKC isozymes in protection by ethanol.
AIM B. Using genetically modified mice (with overexpressed or knockout genes affecting PKC signaling), they will develop a mouse model of ethanol-induced cardioprotection using (1) isolated adult cardiac myocytes, (2) isolated intact heart, and (3) intact animals to determine the time of exposure and dosage of ethanol that provides maximum cardioprotection from ischemia by ethanol and the role of PKC isozymes in this protection.
AIM C. The investigators plan to identify downstream effectors of PKC-mediated and ethanol-induced protection. Specifically, they will examine the role of MAPKs in this process. Together, these studies will help determine the time and dosage of ethanol exposure that provide cardioprotection and help elucidate the molecular basis for cardioprotection by ethanol.
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