Epidemiological studies have shown that light-to-moderate drinkers of alcoholic beverages or red wine (1-4 drinks/day) have significantly lower mortality rates (20-40%) than nondrinkers or heavier drinkers, due to reduced risk for overall CHD-related mortality. Alcohol or red wine components (principal polyphenols) affect a diverse number of biological functions that may afford cardiovascular disease protective benefits, however, the molecular and cellular mechanisms underlying this cardioprotection remain poorly defined and understood. The integrating research theme of this inter-disciplinary Program Project Grant is to identify and define the molecular regulatory mechanisms by which moderate alcohol- or red wine polyphenols affect systemic circulatory components (blood vessels/components, ECs) and myocardial function (cardiomyocytes) that contribute to the cardioprotective benefits attributed to moderate alcohol or red wine consumption. A combination of both in vivo studies with genetically deficient murine models (including PAs -/-, Pmg -/-, PAI-1 -/-, eNOS -/-, iNOS -/-, SOD -/-, apoE-/-) and in vitro studies with cultured cells (human/mouse ECs, myocytes) will be used to decipher some of these protective mechanisms through four integrated research projects, supported by three core units (administrative, tissue culture/plasmid and animalPoioanalysis). Project 1 will study protection through mechanisms of increased EC fibrinolysis, regulated by EC fibrinolytic protein (PAs, PARs, PmgRs) function, expression and gene transcription. Project 2 will study protection through mechanisms of increased EC fibrinolysis, regulated by EC PAI-1 function, expression and gene transcription. Project 3 will study protection through mechanisms of increased NO bioavailability and altered vascular function, regulated by EC eNOS/SOD expression and eNOS gene transcription. Project 4 will study increased NO production/iNOS expression in cardiomyocytes and protection of the mouse heart from ischemic-repeffusion through NO-dependent modulation of cardiac mitochondrial respiratory function. The collective results gleaned from these research projects will provide significant new insights into our understanding of the individual, combined or synergistic roles of these multiple ethanol- /polyphenol-induced cardioprotective mechanisms that underlie and contribute to the decreased risk for thrombosis, atherosclerosis/CHD and the atherothrombotic consequence of MI, thereby reducing overall CHD and CHD-related mortality.
