MECHANISMS OF ETHANOL-INDUCED CARDIOVASCULAR PROTECTION

心血管疾病仍然是美国妇女和妇女死亡的主要原因，因此，更好地了解心脏保护机制可能会带来巨大的健康益处。大量的流行病学数据表明，适度饮酒可以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，这表明它们可能具有共同的但尚未确定的分子机制。酒精对心血管的保护作用可分为两个主要反应：(1)对全身循环成分(血管和血管成分)的影响；(2)对心肌的影响。这项提案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)中度酒精增强血管功能，这是一种心脏保护形式；(2)中度酒精导致血管中一氧化氮合酶(NOS)的诱导；(3)NOS的诱导涉及iNOS和eNOS两种异构体；(4)NO的生物利用度也可能通过诱导超氧化物歧化酶(SOD)而增加；(5)NO的生物利用度增加可能与适度饮酒相关的心血管保护有关。这些数据导致了这样的假设，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中的一个关键事件。这一假说将通过完成以下具体目标来检验：(1)与慢性中度乙醇相关的血管保护事件是由于一氧化氮合酶诱导产生的NO的生物利用度增加而产生的；(2)与慢性中度乙醇相关的血管保护事件是由于超氧化物歧化酶的增加以及随后超氧化物(O2)的减少而导致的.NO的生物利用度的增加。从这些特定目标的实现中获得的信息将为深入了解导致酒精诱导的心血管保护中NO依赖增加的机制提供洞察力。

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.