Vascular Protective Effects of Alcohol - Role of Notch

摘要 -- -- 适度饮酒(Etoh)是心血管疾病的负面风险因素，但准确的 其中涉及的机制尚未阐明。血管内皮细胞是血管疾病发生的关键 (EC)功能障碍或丧失。随后，血管平滑肌细胞(SMC)的生长和迁移 动脉粥样硬化斑块发展中的关键过程，有助于内膜-中膜增厚和血管 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，乙醇对动脉粥样硬化的影响 因此，这些血管细胞具有相当大的临床价值。在这种情况下，Notch信令作为 一个新的潜在的酒精靶子。抑制动脉内皮细胞中的Notch信号释放促炎和 促进动脉粥样硬化发生的促动脉粥样硬化信号。此外，Notch信令驱动着 成年SMC由收缩表型分化为增殖表型。动物模型研究 证明Notch信号在实验诱导的血管损伤后被刺激，并指出 SMC Notch 1在介导新生内膜形成中的优先作用。我们已经证明了酒精可以抑制 抑制Notch信号转导途径促进SMC体外增殖。与之形成明显对比的是，酒精刺激Notch信号 抑制单核细胞趋化蛋白-1的表达。这些数据 强调酒精对血管内皮细胞和血管平滑肌细胞Notch信号的不同作用--刺激和抑制， 分别，并进一步，牵连Notch通路在调节两种醇维持抗- 致动脉粥样硬化的EC表型及其对SMC增殖的抑制作用 协同作用具有抗动脉粥样硬化作用。的确，适量饮酒可以改善血管重构和斑块 在受损的小鼠动脉中形成。最近，在SMC中，我们展示了酒精的一种新的抑制作用 特别是对Notch信号至关重要的γ分泌酶切割活性。现在是我们的初步数据 提示乙醇能增强EC的γ-分泌酶活性。因此，我们提案的中心假设是 适量饮酒通过不同但协同的作用预防动脉粥样硬化的形成 γ-分泌酶水平的Notch信号，在血管平滑肌和内皮细胞中。测试我们的 假设，并描述涉及的机制，我们将使用一种新的体外‘模拟动脉’支架和 在循环应变条件下接种SMC细胞，以及暴露于生理和 人工毛细血管中的病理性剪应力，结合利用转基因小鼠和 动脉粥样硬化的“限流”模型。破译酒精可以预防疾病的机制 心血管疾病具有重要的临床意义，将为这一常见疾病发现新的治疗靶点。 致病和死亡的原因。

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.