NO:Role in Vascular Protection by Polyphenols & Alcohol

饮食成分，如多酚和酒精，对慢性疾病，特别是心血管系统疾病的相互作用，直到最近才出现。这是一个关键领域，因为大量流行病学证据表明，饮用适量的酒精饮料，特别是红葡萄酒，可降低心血管疾病的发病率和与心肌梗死相关的死亡率。这种心血管保护的分子机制仍然不确定，但似乎涉及这些成分与血管壁细胞的复杂相互作用。被用来解释这些保护作用的多酚的主要特性是它们的抗氧化特性。构成这一建议基础的数据表明，多酚作为抗氧化剂的假设得到了有趣的阐述，特别是与乙醇结合使用时。我们认为，关键血管保护酶的浓度和活性的转录调控是增强心血管保护作用的主要原因，并且在与乙醇结合时更为明显。增强内源性细胞保护酶的主要作用是提高一氧化氮（NO）的生物利用度。初步数据表明，膳食多酚和酒精(1)增强一氧化氮依赖性血管功能(2)增加血管中一氧化氮合酶（NOS） mRNA的表达；(3)诱导血管中iNOS和eNOS亚型的蛋白表达；(4)诱导血管超氧化物歧化酶（SOD）；(5)一氧化氮生物可利用性的提高可能与心血管保护有关。这些数据导致了这样的假设：“适度饮酒或饮食中的多酚会增加一氧化氮的生物利用度，并在赋予血管保护方面发挥关键作用”。这一假设将通过完成以下具体目标来检验：(1)膳食多酚和适度酒精诱导一氧化氮化酶增加一氧化氮的生物利用度，从而起到血管保护作用；(2)膳食多酚和适度酒精诱导超氧化物歧化酶（SOD）产生，从而降低超氧化物（O2-）的含量，从而增加一氧化氮的生物利用度，从而起到血管保护作用；(3)补充多酚通过提高一氧化氮的生物利用度并降低对促炎氧化剂的易感性而起到血管保护作用。这些具体目标的完成将有助于深入了解导致NO增加的机制以及这些NO依赖机制在多酚和酒精相关的心血管保护中所起的作用。

The interaction of dietary components, such as the polyphenols and alcohol, on chronic diseases, particularly those of the cardiovascular system, is only recently emerging. This is a key area since considerable epidemiological evidence indicates that consumption of moderate levels of alcoholic beverages, particularly red wine, decreases both the incidence of cardiovascular disease and the mortality associated with myocardial infarction. Molecular mechanisms of this cardiovascular protection remain uncertain but appear to involve complex interactions of these components with cells in the vascular wall. The main attribute of the polyphenols that have been forwarded to explain these protective effects has been their antioxidant properties. Data forming the foundation of this proposal indicate an interesting elaboration of the hypothesis that polyphenols act as antioxidants, particularly in conjunction with ethanol. It is proposed that transcriptional regulation of the concentration and activity of critical vascular protective enzymes makes a major contribution to the enhanced cardiovascular protective effects and is more pronounced in combination with ethanol. The main effect of the enhanced endogenous cytoprotective enzymes is to increase the bioavailability of nitric oxide (NO). Preliminary data shows that dietary polyphenols and alcohol (1) enhance NO-dependent vascular function (2) increase expression of nitric oxide synthases (NOS) mRNA in the vasculature; (3) induce protein expression of both iNOS and eNOS isoforms in the vasculature; (4) induce vascular superoxide dismutases (SOD); and (5) that increased bioavail- ability of NO may be responsible for the cardiovascular protection. These data have led to the hypothesis that "moderate alcohol or dietary polyphenols will increased NO bioavailability and play a pivotal role in conferring vascular protection". This hypothesis will be tested by completion of the following Specific Aims: (1) induction of NOS by dietary polyphenols and moderate alcohol increases bioavailability of NO and results in vascular protection, (2) induction of SOD and a consequent decrease in superoxide (O2-.) by dietary polyphenols and moderate alcohol increases the bioavailability of NO and results in vascular protection, and (3) polyphenol supplementation results in vascular protection due to both increased bioavailability of NO and a consequent decreased susceptibility to pro-inflammatory oxidants. The completion of these specific aims will provide insight into the mechanisms that lead to increased NO and role that these NO-dependent mechanisms play in the cardiovascular protection associated with polyphenols and alcohol.