Mechanisms of Alcohol and Polyphenol Cardioprotection

酒精和多酚的心脏保护机制

• 批准号: 6797827
• 负责人: FRANCOIS M BOOYSE
• 金额: $ 146.25万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797827
• 关键词: alcoholic beverage consumption; cardiovascular disorder prevention; clinical research; cytoprotection; ethanol

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.

描述（由申请人提供）：流行病学研究表明，轻度至中度饮酒者（每天 1-4 杯）的死亡率 (20-40%) 显着低于不饮酒者或重度饮酒者，因为与 CHD 相关的总体死亡率风险降低。酒精或红酒成分（主要多酚）会影响多种生物功能，这些功能可能会提供心血管疾病保护作用，但是，这种心脏保护作用背后的分子和细胞机制仍然知之甚少。这项跨学科计划项目资助的综合研究主题是确定和定义适量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）的分子调节机制，从而有助于因适量饮酒或红酒而产生的心脏保护作用。结合遗传缺陷小鼠模型（包括 PAs -/-、Pmg -/-、PAI-1 -/-、eNOS -/-、iNOS -/-、SOD -/-、apoE-/-）的体内研究和培养细胞（人/小鼠 EC、肌细胞）的体外研究，将通过由三个核心单位支持的四个综合研究项目来破译其中一些保护机制。 （管理、组织培养/质粒和动物毒力分析）。项目 1 将研究通过增加 EC 纤溶蛋白（PA、PAR、PmgR）功能、表达和基因转录调节的 EC 纤溶作用机制来提供保护。项目 2 将通过 EC PAI-1 功能、表达和基因转录调节的增加 EC 纤维蛋白溶解的机制来研究保护作用。项目 3 将通过 EC eNOS/SOD 表达和 eNOS 基因转录调节，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。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。从这些研究项目中收集到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的动脉粥样硬化后果风险降低的基础并有助于降低，从而降低总体CHD和CHD相关死亡率。