Insulin-Like Growth Factor-1 and Atherosclerosis

胰岛素样生长因子 1 与动脉粥样硬化

• 批准号: 7661380
• 负责人: PATRICE DELAFONTAINE
• 金额: $ 37.25万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-05 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661380
• 关键词: Adhesions; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Binding; Blood Circulation; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Cells; Cerebrovascular Disorders; Clinical; Coronary; Development; Down-Regulation; Endocrine; Endothelium; Event; Foam Cells; Functional disorder; Growth Factor; Inflammatory; Infusion procedures; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Lesion; Lipids; Lymphocyte; Mediating; Necrosis; Outcome; Patients; Peripheral; Phenotype; Play; Prevention; Process; Quality of life; Rodent; Role; Rupture; Signal Pathway; Smooth Muscle Myocytes; Stem cells; Stimulus; Surface; Thrombosis; Tunica Adventitia; Western World; Wound Healing; autocrine; cytokine; extracellular; human NOS3 protein; improved; insight; macrophage; monocyte; mortality; nitrosative stress; oxidized low density lipoprotein; paracrine; repaired; response; vascular smooth muscle cell migration; vascular smooth muscle cell proliferation

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.

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，其临床表现很大程度上是由动脉粥样硬化病变的发生、进展和不稳定造成的。氧化低密度脂蛋白 (OxLDL) 是一种关键的促动脉粥样硬化分子，可诱导血管壁和循环细胞中的多种细胞反应，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细胞凋亡增加和 SMC 耗竭中发挥重要作用，从而导致斑块不稳定。啮齿类动物输注 IGF-1 可增加循环内皮祖细胞、减少循环细胞因子、上调内皮一氧化氮合酶并减少动脉粥样硬化斑块负担。这些发现表明 IGF-1 还可能将斑块成分改变为更稳定且炎症更少的表型。该项目的长期作用是通过深入了解 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： 1. 证明 IGF-1 通过抗氧化作用减少动脉粥样硬化，包括诱导内皮一氧化氮合酶表达和活性、减少炎症细胞因子和预防泡沫细胞形成。 2. 证明IGF-1能够通过刺激血管祖细胞（包括内皮祖细胞（EPC））的募集来促进血管修复，从而减少动脉粥样硬化。 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/旁分泌机制介导的。这些研究将为IGF-1对动脉粥样硬化病理生理学的影响提供关键的机制见解，并为旨在改善冠状动脉、周围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依据。