Mechanisms of Alcohol and Polyphenol Cardioprotection

描述(由申请人提供)：流行病学研究表明，与不饮酒或重度饮酒的人相比，轻度至中度饮酒或红酒(每天1-4杯)的死亡率(20%-40%)显著低于不饮酒者或重度饮酒者，这是因为与CHD相关的总体死亡率降低。酒精或红酒成分(主要多酚)影响多种生物学功能，可能提供心血管疾病保护益处，然而，这种心脏保护的分子和细胞机制仍然缺乏定义和了解。这一跨学科项目资助的综合研究主题是确定和定义适度酒精或红酒多酚影响全身循环组件(血管/组件，ECs)和心肌功能(心肌细胞)的分子调控机制，这些组件有助于适度饮酒或红酒带来的心脏保护益处。通过对遗传缺陷小鼠模型的体内研究(包括PAS-/-、PMG-/-、PAI-1-/-、eNOS-/-、iNOS-/-、SOD-/-、apoE-/-)和体外培养细胞(人/鼠内皮细胞、心肌细胞)的研究相结合，将通过四个综合研究项目来破译其中一些保护机制，并得到三个核心单元(行政、组织培养/质粒和动物分析)的支持。项目1将研究由EC纤溶蛋白(PAS、PARS、PmgRs)功能、表达和基因转录调节的EC纤溶增加的保护机制。项目2将研究由EC PAI-1的功能、表达和基因转录调节的EC纤溶增加的保护机制。项目3将通过增加NO的生物利用度和改变血管功能的机制来研究保护作用，这些机制受EC eNOS/SOD表达和eNOS基因转录的调节。项目4将研究增加心肌细胞中NO的产生/iNOS的表达，以及通过NO依赖的心肌线粒体呼吸功能的调节来保护小鼠心脏免受缺血再灌注的影响。从这些研究项目中收集的集体结果将为我们提供重要的新见解，使我们了解这些由乙醇/多酚诱导的多种心脏保护机制的单独、联合或协同作用，这些机制是降低血栓形成、动脉粥样硬化/冠心病和心肌梗塞的动脉粥样硬化血栓形成风险的基础和贡献，从而降低总体冠心病和冠心病相关死亡率。

DESCRIPTION (provided by applicant): 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.