Insulin-Like Growth Factor-1 and Atherosclerosis

描述(申请人提供)：心血管疾病是西方世界死亡的主要原因，其临床表现很大程度上是由于动脉粥样硬化病变的发展、进展和不稳定造成的。氧化低密度脂蛋白(OxLDL)是一种重要的促动脉粥样硬化分子，可在血管壁和循环细胞中诱导多种细胞反应，包括氧化/亚硝化应激增加、内皮损伤、巨噬细胞转化为泡沫细胞和平滑肌细胞(SMC)凋亡。OxLDL下调血管胰岛素样生长因子-1(IGF-1)和IGF-1受体可能在动脉粥样硬化斑块中SMC凋亡和耗竭增加的过程中起重要作用，从而导致斑块失稳。在啮齿动物体内输注IGF-1可增加循环内皮祖细胞，减少循环细胞因子，上调内皮型一氧化氮合酶，并减轻动脉粥样硬化斑块负担。这些发现表明，IGF-1也可能改变斑块的组成，使其更稳定，炎症更少。该项目的长期作用是了解IGF-1如何通过深入了解其抗氧化、抗炎和促进修复的作用来影响动脉粥样硬化斑块的发展和稳定性。具体目标是： 1.证明IGF-1通过诱导内皮型一氧化氮合酶的表达和活性、减少炎性细胞因子和防止泡沫细胞的形成等抗氧化作用来减轻动脉粥样硬化。 2.证明IGF-1通过刺激包括内皮祖细胞(EPC)在内的血管前体细胞的募集来促进血管修复，从而减轻动脉粥样硬化。 3.证明IGF-1的抗动脉粥样硬化作用是通过内分泌和自分泌/旁分泌机制实现的。这些研究将为IGF-1在动脉粥样硬化的病理生理学中的作用提供关键的机制见解，并为旨在改善冠心病、外周血管和脑血管疾病患者的临床结果和生活质量的新疗法提供理论基础。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of mortality in the Western world and its clinical manifestations result in large part from atherosclerotic lesion development, progression and destabilization. Oxidized low density lipoprotein (OxLDL) is a key pro-atherogenic molecule which induces a variety of cellular responses in the vascular wall and potentially in circulating cells, including increased oxidative/nitrosative stress, endothelial damage, transformation of macrophages into foam cells and apoptosis of smooth muscle cells (SMC). OxLDL downregulation of vascular insulin-like growth factor-1 (IGF-1) and IGF-1 receptors may play an important role in increased apoptosis and depletion of SMC in atherosclerotic plaque, contributing to plaque destabilization. IGF-1 infusion in rodents increases circulating endothelial progenitor cells, reduces circulating cytokines, upregulates endothelial nitric oxide synthase and reduces atherosclerotic plaque burden. These findings suggest that IGF-1 may also alter plaque composition to a more stable and less inflammatory phenotype. The long-term role of this project is to understand how IGF-1 impacts atherosclerotic plaque development and stability by obtaining insights into its anti-oxidant, anti-inflammatory and pro-repair effects. Specific aims are to: 1. Demonstrate that IGF-1 reduces atherosclerosis via an anti-oxidant effect that includes induction of endothelial nitric oxide synthase expression and activity, reduction in inflammatory cytokines and prevention of foam cell formation. 2. Demonstrate that IGF-1 reduces atherosclerosis via its ability to promote vascular repair by stimulating the recruitment of vascular progenitor cells, including endothelial progenitor cells (EPC). 3. Demonstrate that the anti-atherosclerotic effects of IGF-1 are mediated via endocrine and autocrine/ paracrine mechanisms. These studies will provide key mechanistic insights into the effects of IGF-1 on the pathophysiology of atherosclerosis and provide a rationale for new therapies targeted at improving the clinical outcome and quality of life of patients afflicted with coronary, peripheral vascular and cerebrovascular disease.