Insulin-Like Growth Factor-1 and Atherosclerosis

描述(申请人提供)：动脉粥样硬化的临床后遗症很广泛，导致心血管疾病成为西方世界死亡的主要原因。动脉粥样硬化的急性表现大多是由于斑块破裂引起的。导致斑块破裂的机制包括炎症增加，特别是在斑块的肩部，以及血管平滑肌细胞(VSMC)枯竭导致纤维帽变薄。氧化低密度脂蛋白(OxLDL)在动脉粥样硬化的各个阶段都发挥着重要作用，是泡沫细胞聚集、巨噬细胞、内皮细胞和VSMC凋亡的主要触发因素。胰岛素样生长因子-1(IGF-1)是包括VSMC在内的许多细胞的有效生存因子。在体外，OxLDL可降低IGF-1及其受体(IGF-1R)的表达。该项目的长期目标是确定IGF-1系统在OxLDL触发VSMC凋亡和加速动脉粥样硬化病变发展中的作用。研究OxLDL对VSMC中IGF-1R生存通路的影响。2.研究VSMC靶向缺失IGF-1R对ApoE基因敲除小鼠动脉粥样硬化病变形成的影响。3.研究VSMC靶向过表达IGF-1R对ApoE-/-(基因敲除)小鼠动脉粥样硬化病变形成的影响。这项提案的主要焦点将是确定IGF-1是否通过其IGF-1R作用于细胞，从OxLDL诱导的细胞凋亡中拯救细胞。这些研究将为人类动脉平滑肌细胞的凋亡机制提供重要的新信息，为预防急性心血管事件提供新的治疗靶点。

DESCRIPTION (provided by applicant): The clinical sequelae of atherosclerosis are broad and result in cardiovascular disease being the leading cause of mortality in the Western world. Acute manifestations of atherosclerosis result in most instances from plaque rupture. Mechanisms leading to plaque rupture include increased inflammation, particularly in the shoulder area of the plaque, and depletion of vascular smooth muscle cells (VSMC) resulting in fibrous cap thinning. Oxidized LDL (OxLDL) plays an important role in all stages of atherosclerosis, and is a primary trigger for foam cell accumulation, and apoptosis of macrophages, endothelial cells and VSMC. Insulin-like Growth Factor-1 (IGF-1) is a potent survival factor for many cells including VSMC. In vitro, OxLDL decreases IGF-1 and IGF-1receptor (IGF-1 R) expression. The long-term goal of this project is to determine the role of the IGF-1 system in the ability of OxLDL to trigger VSMC apoptosis and accelerate atherosclerotic lesion development. Specific aims are: 1. Study the effect of OxLDL on the IGF-1R survival pathway in VSMC. 2. Study the effect of VSMC-targeted deletion of the IGF-1R on atherosclerotic lesion formation in ApoE knockout mice. 3. Study the effect of VSMC-targeted overexpression of the IGF-1R on atherosclerotic lesion formation in ApoE-/-(knockout) mice. The primary focus of this proposal will be to determine if IGF-1 acting through it's IGF-1R can rescue cells from OxLDL induced apoptosis. These studies will provide important new information regarding mechanisms of apoptosis in human arterial smooth muscle cells, offering new therapeutic targets for the prevention of acute cardiovascular events.