Mechanisms of Alcohol and Polyphenol Cardioprotection

描述（由申请人提供）：流行病学研究表明，轻度至中度饮酒的酒精饮料或红葡萄酒（1-4杯/天）的死亡率（20-40%）显著低于不饮酒者或重度饮酒者，因为总体CHD相关死亡率的风险降低。酒精或红葡萄酒成分（主要多酚）影响多种生物功能，可能提供心血管疾病的保护作用，然而，这种心脏保护的分子和细胞机制仍然缺乏定义和理解。该跨学科计划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成分（血管/成分，EC）和心肌功能（心肌细胞）的分子调控机制，这些机制有助于适度酒精或红酒消费带来的心脏保护益处。两种体内研究与遗传缺陷小鼠模型的组合（包括PA-/-、Pmg -/-、派-1 -/-、eNOS-/-、iNOS -/-、SOD -/-、apoE-/-）和培养细胞的体外研究（人/小鼠内皮细胞、肌细胞）将通过四个综合研究项目来破译其中的一些保护机制，（管理、组织培养/质粒和动物分析）。项目1将通过EC纤溶蛋白（PA，PAR，Pmgr）功能，表达和基因转录调节EC纤溶增加的机制来研究保护作用。项目2将研究通过EC纤溶酶原激活物抑制派-1的功能、表达和基因转录调节增加EC纤溶酶的机制来保护。项目3将通过增加NO生物利用度和改变血管功能的机制来研究保护作用，这些机制由EC eNOS/SOD表达和eNOS基因转录调节。项目4将研究心肌细胞中NO产生/iNOS表达的增加，以及通过NO依赖性调节心脏线粒体呼吸功能来保护小鼠心脏免受缺血再灌注损伤。从这些研究项目中收集的集体结果将为我们理解这些多种乙醇/多酚诱导的心脏保护机制的个体，组合或协同作用提供重要的新见解，这些机制是血栓形成，动脉粥样硬化/CHD和MI的动脉粥样硬化血栓形成后果的风险降低的基础和贡献，从而降低总体CHD和CHD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.