Vascular Protective Effects of Alcohol - Role of Notch

酒精的血管保护作用 - Notch 的作用

• 批准号: 9977944
• 负责人: EILEEN M. REDMOND
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977944
• 关键词: Adult; Affect; Alcohol consumption; Alcohols; Angioplasty; Animal Model; Antiatherogenic; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; Blood capillaries; CCL2 gene; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Proliferation; Cells; Clinical; Data; Development; Disease; Drug Targeting; Endothelial Cells; Endothelium; Environment; Ethanol; Exposure to; Functional disorder; Generations; Growth; Homeostasis; In Vitro; Incubators; Industry; Inflammatory; Institutes; Intellectual Property; Investigation; Laboratories; MAPK8 gene; Maintenance; Mediating; Medical center; Membrane Microdomains; Modeling; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Pathologic; Pathology; Pathway interactions; Periodicity; Phenotype; Physicians; Physiological; Play; Process; Regulation; Reporting; Repression; Role; Signal Transduction; Smooth Muscle Myocytes; Stenosis; Stents; Stimulus; Testing; Transgenic Mice; Translational Research; Vascular Endothelial Cell; Vascular Endothelium; Vascular Smooth Muscle; Work; alcohol abuse therapy; alcohol effect; atherogenesis; atheroprotective; attenuation; base; cardiovascular disorder therapy; cardiovascular risk factor; caveolin 1; clinically relevant; clinically significant; design; disability; epidemiology study; gamma secretase; glycogen synthase kinase 3 beta; in vivo; injured; innovation; interest; intimal medial thickening; migration; mimetics; mortality; new therapeutic target; notch protein; novel; novel therapeutics; oxidized low density lipoprotein; protective effect; restenosis; shear stress; vascular injury

Abstract     Moderate consumption of alcohol (EtOH) is a negative risk factor for cardiovascular disease but the precise mechanisms involved have not been elucidated. Pivotal to the initiation of vessel disease is endothelial cell (EC) dysfunction or loss. Subsequently, the growth and migration of vascular smooth muscle cells (SMC) are key processes in atherosclerotic plaque development, contributing to intima-medial thickening and vessel stenosis. Given the key role of both EC and SMC in the pathophysiology of atherosclerosis, effects of EtOH on these vascular cells are, thus, of considerable clinical interest. In this context Notch signaling has emerged as a novel potential target for alcohol. Repression of Notch signaling in arterial EC unlocks pro-inflammatory and pro-atherogenic signals that contribute to the initiation of atherosclerosis. Moreover, Notch signaling drives the differentiation of adult SMC from a contractile to a proliferative phenotype. Studies in animal models demonstrate that Notch signaling is stimulated following experimentally induced vascular injury, and point to a preferential role for SMC Notch 1 in mediating neointimal formation. We have shown that alcohol restrains SMC proliferation in vitro by inhibiting Notch signaling. In apparent contrast, alcohol stimulates Notch signaling and angiogenic activity in EC, while inhibiting monocyte chemoattractant protein-1 expression. These data highlight a differential effect of alcohol on Notch signaling in vascular EC and SMC - stimulatory and inhibitory, respectively, and further, implicate the Notch pathway in mediating both alcohols maintenance of an anti- atherogenic EC phenotype and it's attenuation of SMC proliferation, actions that might be considered synergistically atheroprotective. Indeed, moderate alcohol consumption ameliorates remodeling and plaque formation in injured mouse arteries. Recently, in SMC, we demonstrated a novel inhibitory effect of alcohol specifically on the γ-secretase cleavage activity that is critical for Notch signaling.  Our preliminary data now indicate that EtOH enhances γ-secretase activity in EC. Therefore, the central hypothesis of our proposal is that moderate alcohol consumption protects against atherogenesis by differential yet synergistic effects on Notch signaling at the level of γ-secretase, in vascular smooth muscle and endothelial cells. To test our hypothesis, and delineate the mechanisms involved, we will use a novel in vitro `mock artery' stented and seeded with SMC cells under cyclic strain conditions, as well as endothelial cells exposed to physiologic and pathologic shear stresses in artificial capillaries, in conjunction with in vivo studies utilizing transgenic mice and a `flow-restriction' model of atherosclerosis. Deciphering the mechanisms whereby alcohol may protect against cardiovascular disease is of major clinical significance and will uncover new therapy targets for this common cause of morbidity and mortality.

抽象的     适度的酒精（ETOH）是心血管疾病的负危险因素，但精度 涉及的机制尚未阐明。血管疾病倡议的关键是内皮细胞 （EC）功能障碍或损失。随后，血管平滑肌细胞（SMC）的生长和迁移是 动脉粥样硬化斑块发育中的关键过程，有助于内膜媒体增厚和血管 狭窄。鉴于EC和SMC在动脉粥样硬化的病理生理学中的关键作用，ETOH对 因此，这些血管细胞具有可考虑的临床意义。在这种情况下，Notch信令已出现为 酒精的新型潜在目标。在动脉EC中抑制Notch信号传导，解锁促炎和 促成动脉粥样硬化的倡议的亲动脉粥样硬化信号。此外，Notch信号驱动 成年SMC从收缩的分化到增殖表型。动物模型研究 证明在实验诱导的血管损伤后刺激Notch信号传导，并指向 SMC Notch 1在介导新内膜形成中的优先作用。我们已经表明酒精限制 通过抑制Notch信号传导，在体外SMC增殖。显然，酒精会刺激Notch信号传导 EC中的血管生成活性，同时抑制单核细胞趋化剂蛋白-1表达。这些数据 突出显示酒精对血管EC和SMC刺激和抑制性的Notch信号传导的差异作用， 并且进一步牵涉到缺口途径，用于介导两种醇的抗 - 动脉粥样硬化的EC表型及其对SMC增殖的衰减，可能被认为的作用 协同的动脉保护性。实际上，适度的饮酒可以改善重塑和斑块 受伤的小鼠动脉形成。最近，在SMC中，我们证明了酒精的新型抑制作用 特别是关于凹槽信号传导至关重要的γ-分泌酶裂解活性。我们的初步数据 表明ETOH增强了EC中的γ-分泌酶活性。因此，我们提议的核心假设是 适度的酒精消耗可以通过差异而协同的影响来防止动脉粥样硬化 在γ-分泌酶水平，血管平滑肌和内皮细胞中的Notch信号传导。测试我们的 假设，并描述所涉及的机制，我们将使用一个新颖的体外“模拟动脉”支架和 在循环应变条件下用SMC细胞播种，以及暴露于生理学和的内皮细胞 人造毛细血管中的病理剪切应力以及利用转基因小鼠和的体内研究 动脉粥样硬化的“流动限制”模型。破译酒精可能预防的机制 心血管疾病具有重要的临床意义，并将发现这种常见的新疗法靶标 发病率和死亡率的原因。