ACTION OF ALCOHOL & QUERCETIN ON ANTI-ATHEROGENIC FACTORS & ATHEROGENESIS

描述（由申请人提供）：氧化低密度脂蛋白（OxLDL）在动脉内膜的积累导致动脉粥样硬化。相反，HDL通过其酶对氧磷酶（PON）破坏OxLDL来防止动脉粥样硬化。虽然适量饮用葡萄酒对心脏有保护作用，但葡萄酒中乙醇和槲皮素成分对致动脉粥样硬化（AAA）因子的益处尚不明确。在动物模型中，槲皮素和/或乙醇对AAA因子（PON状态、HDL抑制LDL氧化的能力、LDL颗粒大小和主动脉中OxLDL水平）与主动脉动脉粥样硬化程度（主动脉形态测量学分析）可能产生的有益影响将是一项重大进展和临床相关的新方法。这种直接关联在前瞻性人体试验中是困难的。LDLR-/-小鼠是一种极好的模型，在含胆固醇的饮食中迅速发展为动脉粥样硬化。这使得系统地评估酒精/槲皮素不仅对AAA因子的影响，而且对动脉粥样硬化程度的影响作为时间的函数。PI有以下初步数据支持这一建议：槲皮素喂养8周后，LDLR-/-小鼠血清和肝脏PON活性及肝脏PON mRNA水平均显著高于对照组。2. 与对照组相比，槲皮素喂养的LDLR-/-小鼠的HDL对LDL氧化的保护作用更强（这是由于HDL的PON成分）。4. 饲喂致动脉粥样硬化性饮食8周后，LDL-/-小鼠血清和肝脏PON活性显著降低，肝脏PON mRNA水平显著降低，并伴有主动脉斑块扩大。5. 中度酒精喂养8周：LDLR-/-小鼠血清和肝脏PON活性升高。PI的具体目的是描述酒精/槲皮素对AAA因子和动脉粥样硬化的作用：目的1。最佳膳食浓度。目标2。最佳喂食时间。目标3。可能的作用机制。目标4。对hdl抗氧化性能的影响。使用SAS软件对数据进行统计分析。因此，从逻辑上讲，这项探索性研究将导致一项控制良好的人体试验，以最终证明适度酒精/槲皮素通过调节AAA因子在心脏保护方面可能的独立益处。因此，这项对酒精/槲皮素作用的机制和临床相关性研究具有有效预防心血管疾病的潜力。

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.