MECHANISMS OF ETHANOL-INDUCED CARDIOVASCULAR PROTECTION

在美国，心血管疾病仍然是导致男女死亡的主要原因，因此，更好地了解心脏保护机制对健康的好处可能是巨大的。相当多的流行病学数据表明，适度饮酒可降低心血管疾病的发病率和与心肌梗死相关的死亡率。与适度饮酒相关的心脏保护在许多方面类似于晚期预适应，表明它们可能具有共同的，但尚未确定的分子机制。酒精的心血管保护作用可分为两个主要反应，(1)对体循环成分（血管和血液成分）的作用，(2)对心肌的作用。这一建议将侧重于描述酒精对血管系统的心脏保护作用的机制。初步数据显示(1)适度饮酒可增强血管功能，起到保护心脏的作用；(2)适量酒精可诱导血管中一氧化氮合酶（NOS）的产生；(3) NOS的诱导涉及iNOS和eNOS两种亚型；(4)生物利用度。一氧化氮也可通过诱导超氧化物歧化酶（SOD）而增加；(5)提高了生物利用度。NO可能与适量饮酒相关的心血管保护有关。这些数据导致了一种假设，即一氧化氮（NO）生物利用度的增加是与慢性中度酒精相关的血管和心脏保护事件的关键事件。这一假设将通过完成以下具体目标来验证：(1)与慢性中度乙醇相关的血管保护事件是由于生物利用度的增加。一氧化氮合酶的诱导和一氧化氮的增加所产生的一氧化氮。NO和(2)与慢性适度乙醇相关的血管保护事件是由于生物利用度的增加。由超氧化物歧化酶增加和随后的超氧化物（O2）减少引起的一氧化氮。从这些具体目标的实现中获得的信息将提供对导致增加的机制的见解。酒精诱导的心血管保护中的no依赖机制。

Cardiovascular disease remains the leading cause of mortality of both women and women in the United States, so the health benefits gained from a better understanding of the mechanisms of cardioprotection could be enormous. Considerable epidemiological data indicates that moderate alcohol consumption decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. The cardioprotection associated with moderate alcohol consumption is analogous in many ways to late phase pre-conditioning indicating that they may share common, but yet undefined, molecular mechanisms. The cardiovascular protective effects of alcohol can be categorized into two major responses, (1) effects on systemic circulatory components (blood vessels and blood components), (2) effects on myocardium. This proposal will focus on delineating the mechanisms of the cardio-protective effects of alcohol on the vasculature. Preliminary data show that (1) moderate alcohol enhances vascular function, a form of cardioprotection; (2) moderate alcohol results in induction of nitric oxide synthases (NOS) in the vasculature; (3) induction of NOS involves two isoforms, iNOS and eNOS; (4) bioavailability of .NO may also be increased by induction of superoxide dismutases (SOD); (5) increased bioavailability of .NO may be responsibl4e for the cardiovascular protection associated with moderate alcohol consumption. These data have led to the hypothesis that increased nitric oxide (NO) bioavailability is a critical event in the vascular and cardioprotective events associated with chronic moderate alcohol. This hypothesis will be tested by completion of the following Specific Aims: (1) the vascular protective events associated with chronic moderate ethanol are due to the increased bioavailability of .NO resulting from induction of nitric oxide synthases and increased production of .NO and (2) the vascular protective events associated with chronic moderate ethanol are due to the increased bioavailability of .NO resulting from increased superoxide dismutase and a consequent decrease in superoxide (O2). The information gained from the accomplishment of these specific aims will provide insights into the mechanism which lead to increased .NO-dependent mechanisms in alcohol-induced cardiovascular protection.