Insulin-Like Growth Factor-1 and Atherosclerosis

描述（由申请人提供）：心血管疾病是西方世界死亡的主要原因，其临床表现在很大程度上是由动脉粥样硬化病变的发展、进展和不稳定引起的。氧化低密度脂蛋白（OxLDL）是一种关键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细胞凋亡增加和SMC耗竭中发挥重要作用，促进斑块不稳定。IGF-1输注可增加循环内皮祖细胞，减少循环细胞因子，上调内皮一氧化氮合酶，减轻动脉粥样硬化斑块负担。这些发现表明，IGF-1也可能改变斑块组成，使其更稳定，炎症更少。该项目的长期作用是通过了解IGF-1的抗氧化、抗炎和促修复作用，了解IGF-1如何影响动脉粥样硬化斑块的发展和稳定性。具体目标是：

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.