ACTION OF ALCOHOL/QUERCETIN ON ANTI-ATHEROGENIC FACTOR

描述(由申请人提供)：氧化型低密度脂蛋白(OxLDL)在动脉内膜中积聚会导致动脉粥样硬化。相反，高密度脂蛋白通过其酶对氧磷酶(PON)破坏氧化低密度脂蛋白来预防动脉粥样硬化。虽然适量饮用葡萄酒可以保护心脏，但葡萄酒中的乙醇和槲皮素成分对遗传/抗动脉粥样硬化(AAA)因子的好处还没有明确的定义。一项重大的进展和临床相关的新方法将是在动物模型中将槲皮素和/或乙醇对AAA因子(PON状态、高密度脂蛋白抑制低密度脂蛋白氧化的能力、低密度脂蛋白颗粒大小和氧化低密度脂蛋白水平)的可能有益影响与动脉粥样硬化的程度(主动脉的形态计量分析)直接相关。在预期的人体试验中，如此直接的相关性是困难的。低密度脂蛋白受体-/-小鼠是一个极好的模型，它能在高胆固醇饮食中迅速形成动脉粥样硬化。这使得能够系统地评估酒精/栎素不仅对AAA因素的影响，而且还对动脉粥样硬化的程度随时间的变化进行评估。PI有以下初步数据支持这一建议：1.与对照组相比，灌胃8周的LDLR-/-小鼠血清和肝脏PON活性以及肝脏PON mRNA水平显著上调。2.LDLR-/-小鼠的高密度脂蛋白与对照组的高密度脂蛋白相比，具有更强的抗低密度脂蛋白氧化能力(这是由于高密度脂蛋白的PON成分所致)。4.喂饲致动脉粥样硬化饲料8周可显著降低低密度脂蛋白转基因小鼠血清和肝脏PON活性及肝脏PON基因表达水平，并伴有广泛的主动脉斑块形成。5.适量饮酒8周：LDLR-/-小鼠血清和肝脏PON活性升高。PI有这些特定的目的来描述酒精/槲皮素在AAA因子和动脉粥样硬化中的作用：目的1.最佳饮食浓度。目的2.最佳投喂时间。目标3.可能的机制/行动的S目的4.对高密度脂蛋白抗氧化性能的影响。数据将使用SAS软件进行统计分析。因此，这项探索性研究将在逻辑上导致一项良好对照的人体试验，以最终证明适度酒精/槲皮素可能通过调节AAA因子在心脏保护中的独立益处。因此，这项关于酒精/栎素作用的机械性和临床相关性研究有可能有效地预防心血管疾病。

DESCRIPTION (provided by applicant): Accumulation of oxidized low density lipoproteins (OxLDL) in the intima of arteries causes atherosclerosis. In contrast, HDL protects against atherosclerosis via its enzyme paraoxonase (PON) that destroys OxLDL. Whereas moderate wine consumption is cardioprotective, the benefits of both ethanol and quercetin components of wine on herogenic/antiatherogenic (AAA) factors are not clearly defined. A major advancement and clinically relevant new approach would be to directly correlate the possible beneficial effects of quercetin and/or ethanol on AAA factors (PON status, HDL's capacity to inhibit LDL oxidation, LDL particle size, and OxLDL level in aorta) with the extent of atherosclerosis in the aorta (morphometric analysis of aorta) in an animal model. Such a direct correlation is difficult in a prospective human trial. LDLR-/- mouse is an excellent model that promptly develops atherosclerosis on a cholesterol cholatecontaining diet. This enables a systematic evaluation of the effects of alcohol/quercetin not only on AAA factors, but also on the extent of atherosclerosis as a function of time. PI has the following preliminary data in support of this proposal: 1. Serum and liver PON activity and liver PON mRNA level were significantly up egulated in LDLR-/- mice fed quercetin for 8 weeks compared to the controls. 2. HDLs from quercetin-fed LDLR-/- mice were more protective against LDL oxidation (this was shown to be due to HDL's PON component) compared to the HDLs from controls. 4. Feeding atherogenic diet for 8 weeks markedly decreased serum and liver PON activity and liver PON mRNA level coupled with extensive aortic plaques in LDL-/- mice. 5. Moderate alcohol feeding for 8 weeks: increased serum & liver PON activity in LDLR-/- mice. PI has these specific aims to delineate the action of alcohol/quercetin on AAA factors and atherosclerosis: Aim 1. Optimal dietary concentration. Aim 2. Optimal time of feeding. Aim 3. Possible Mechanism/s of Action. Aim 4. Effects on antioxidant Property of HDLs. The data will be statistically analyzed using SAS software. Thus, this exploratory study would logically lead to a well-controlled human trial to conclusively prove the possible independent benefits of moderate alcohol/quercetin in cardioprotection via the regulation of AAA factors. Therefore, this mechanistic and clinically releyent study on the actions of alcohol/quercetin has the potential to effectively protect against cardiovascular diseases.