ACTION OF ALCOHOL/QUERCETIN ON ANTI-ATHEROGENIC FACTOR

酒精/槲皮素对抗动脉粥样硬化因子的作用

• 批准号: 7146990
• 负责人: RAJ M LAKSHMAN
• 金额: $ 18.11万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146990
• 关键词: alcoholic beverage consumption; alcoholic beverages; antiatherogenic agent; antioxidants; aorta; atherosclerosis; cardiovascular disorder risk; diet route /schedule; dietary constituent; enzyme activity; esterase; ethanol; genetic transcription; high density lipoproteins; high performance liquid chromatography; laboratory mouse; liver metabolism; low density lipoprotein; messenger RNA; nuclear runoff assay; nutrition related tag; oxidation; pathologic process; polymerase chain reaction; quercetin; statistics /biometry

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.

描述（由申请人提供）：在动脉内膜中氧化的低密度脂蛋白（OXLDL）的积累会引起动脉粥样硬化。相比之下，HDL通过破坏OXLDL的酶（PON）来预防动脉粥样硬化。虽然中等葡萄酒的消耗是心脏保护性的，但葡萄酒的乙醇和槲皮素成分在发源/抗动脉粥样硬化（AAA）因子上的好处尚未明确定义。 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.在前瞻性人类试验中，这种直接相关性很困难。 LDLR - / - 小鼠是一个出色的模型，可迅速在胆固醇胆固醇饮食上发展动脉粥样硬化。这不仅可以系统地评估酒精/槲皮素对AAA因素的影响，而且还可以对动脉粥样硬化随时间的影响进行系统评估。 PI具有以下支持该提案的初步数据：1。血清和肝脏PON活性和肝脏PON mRNA水平在LDLR - / - 小鼠中显着上升了槲皮素，与对照组相比，饲喂槲皮素8周。 2。来自槲皮素喂养的LDLR - / - 小鼠的HDL对LDL氧化具有更大的保护作用（这证明是由于HDL的PON成分引起的），与对照组的HDL相比。 4。喂养动脉粥样硬化饮食8周显着降低了血清和肝脏pON活性，肝脏pON mRNA水平以及LDL - / - 小鼠中广泛的主动脉斑的伴侣。 5。中度酒精喂养8周：LDLR - / - 小鼠中的血清和肝pON活性增加。 PI具有这些特定的目的，目的是描述酒精/槲皮素对AAA因素和动脉粥样硬化的作用：目标1。最佳饮食浓度。目标2。喂食的最佳时间。目标3。可能的机制/作用机理。目标4。对HDLS抗氧化特性的影响。数据将使用SAS软件进行统计分析。因此，这项探索性研究在逻辑上将导致一项良好的人类试验，以最终证明通过调节AAA因素，在心脏保护中可能具有中度酒精/槲皮素的独立益处。因此，这项关于酒精/槲皮素作用的机械性和临床上的研究可能有效预防心血管疾病。