Drinking Pattern and Atherosclerosis

饮酒方式与动脉粥样硬化

• 批准号: 8456437
• 负责人: Ekaterina P. Hatch
• 金额: $ 5.57万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456437
• 关键词: Acetaldehyde; Adopted; Adult; Agreement; Alcohol consumption; Alcohol dehydrogenase; Alcohols; Antiatherogenic; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Attenuated; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cholesterol; Clinical; Complex; Consumption; Coronary artery; Data; Development; Employee Strikes; Enzymes; Epidemiologic Studies; Equilibrium; Ethanol; Functional disorder; Gel; Gene Expression; Growth; Healthcare; Human; In Vitro; Injury; Ischemic Stroke; Knock-out; Medial; Mediating; Metabolism; Molecular; Morbidity - disease rate; Myocardial Infarction; Notch Signaling Pathway; Pathogenesis; Pathway interactions; Pattern; Play; Pluronics; Process; Publishing; Regulation; Reporting; Risk Factors; Role; Signal Transduction; Smooth Muscle Myocytes; Time; Weight Gain; alcohol abuse therapy; alcohol effect; attenuation; binge drinking; cardiovascular disorder therapy; cell growth; design; drinking; drinking behavior; expression vector; in vivo; innovation; loss of function; migration; monocyte; mortality; mouse model; notch protein; novel; protective effect; receptor; research study; restenosis

DESCRIPTION (provided by applicant): Epidemiologic studies point to a complex association between alcohol and cardiovascular disease (CVD). Frequent moderate consumption of alcohol, e.g., 1-2 drinks per day, is a negative risk factor for atherosclerosis and its clinical sequelae myocardial infarction and ischemic stroke. On the other hand, binge drinking, i.e., consuming 5 or more drinks in a relatively short time period, is associated with increased CVD and associated mortality. The balance between alcohol and its primary metabolite, acetaldehyde, may be critical in mediating these seemingly opposite effects of the two drinking patterns. In agreement with epidemiologic studies, striking differential effects of daily moderate and binge alcohol (ethanol, EtOH) consumption on atherosclerotic plaque development, cholesterol levels and weight gain in a mouse model have recently been described. Intriguingly, the precise signaling and molecular mechanisms whereby alcohol elicits its cardiovascular effects, good and bad, have not yet been elucidated. One potentially novel target for alcohol is the Notch signaling pathway, as it is emerging that Notch plays a pivotal role in the differentiation of adul vascular smooth muscle cells (SMC), whose growth and migration are key processes in the pathophysiology of atherosclerosis and in restenosis. The expression of several components of the Notch pathway are enhanced following experimentally induced vascular injury while preferential inhibition of Notch 1, rather than Notch 3 attenuates neointimal formation. This lab's recently published data support an inhibitory effect of daily moderate alcohol treatment on SMC Notch 1 receptor levels and downstream target gene expression, concomitant with inhibition of SMC proliferation in vitro and marked attenuation of neointimal development and medial thickening in vivo. Interestingly, differential effects of alcohol and its metabolite, acetaldehyde on monocyte function have been reported. Moreover, our preliminary data now suggest that in apparent contrast to ethanol, acetaldehyde stimulates Notch expression and proliferation in SMC. Therefore, the central hypothesis of our application is that 'daily moderate' and 'binge' alcohol consumption have opposite effects on atherosclerotic plaque development mediated by differential effects of ethanol (anti-atherogenic), and its metabolite acetaldehyde (pro-atherogenic), on Notch signaling in vascular SMC. Because the mortality from cardiovascular disease is so high, deciphering the mechanisms whereby alcohol can either protect or exacerbate it is clearly of major clinical importance and significance.

描述（由申请人提供）：流行病学研究表明酒精与心血管疾病（CVD）之间存在复杂的关联。频繁的中度饮酒量，例如每天1-2饮料，是动脉粥样硬化及其临床后遗症心肌梗死和缺血性中风的负危险因素。另一方面，暴饮暴食，即在相对较短的时间内食用5种或更多饮料，与CVD和相关死亡率的增加有关。酒精与其主要代谢产物乙醛之间的平衡对于介导两种饮用模式的这些看似相反的影响可能至关重要。最近已经描述了小鼠模型中的每日中度和暴饮暴食（乙醇，ETOH）消耗对动脉粥样硬化斑块发育，胆固醇水平和体重增加的每日中等和暴饮暴食（乙醇）消耗的差异影响的一致。有趣的是，酒精引起其心血管效应（好与坏）的精确信号传导和分子机制尚未得到阐明。酒精的一个潜在新颖的目标是Notch信号通路，因为Notch的出现在纳尔血管平滑肌细胞（SMC）的分化中起关键作用，其生长和迁移是动脉粥样硬化病理生理学的关键过程。在实验诱导的血管损伤后，在优先抑制Notch 1的情况下，增强了Notch途径的几个成分的表达，而不是Notch 3减弱了新的形成。这个实验室 最近发表的数据支持每日中度酒精治疗对SMC Notch 1受体水平和下游靶基因表达的抑制作用，这与体外抑制SMC增殖的抑制作用，并明显地衰减了新内膜发育和体内内侧增厚。有趣的是，据报道，酒精及其代谢物，乙醛对单核细胞功能的差异作用。此外，我们的初步数据现在表明，与乙醇相比，乙醛刺激了SMC中的凹口表达和增殖。因此，我们应用的核心假设是，“每日中度”和“暴饮暴食”的饮酒对乙醇（抗动脉粥样硬化）的差异作用介导的动脉粥样硬化斑块的发育及其代谢产物乙醛（促动脉粥样硬化）对血管SMC中的Notch信号传导。由于心血管疾病的死亡率如此之高，因此破译了酒精可以保护或加剧的机制，显然具有重要的临床重要性和意义。