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: 8575338
• 负责人: PATRICE DELAFONTAINE
• 金额: $ 36.87万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575338
• 关键词: Actins; Acute; Adhesions; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Apolipoprotein E; Apoptosis; Arachidonate 15-Lipoxygenase; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Backcrossings; Biological Availability; Biology; Blood Vessels; CCR1 gene; Cardiovascular system; Cell Cycle; Chemotaxis; Collagen; Collagen Type I; Contractile Proteins; Data; Development; Endocrine; Endothelium; Event; Extracellular Matrix; Foam Cells; Frequencies; Genetic; Genotype; Goals; Grant; Growth Factor; Human; IGF1R gene; In Vitro; Incidence; Inflammatory; Infusion procedures; Injury; Innovative Therapy; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Integrins; Internal Ribosome Entry Site; Knock-out; Knockout Mice; Lesion; Lipids; Mechanics; Mediating; Metallothionein; Modeling; Mouse Strains; Mus; Myocardial Infarction; Names; Necrosis; Outcome; Oxidative Stress; Peptide Hydrolases; Phenotype; Pregnancy-Associated Plasma Protein-A; Process; Regulation; Reporting; Research; Role; Rupture; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Testing; Tetracyclines; Transgenic Mice; Translating; Translational Research; Up-Regulation; atherogenesis; autocrine; base; cell type; chemokine; chemokine receptor; gain of function; innovation; insight; lipoprotein lipase; loss of function; macrophage; monocyte; mouse model; novel; overexpression; paracrine; promoter; research study

DESCRIPTION (provided by applicant): The role of growth factors such as insulin-like growth factor-1 (IGF-1) in atherogenesis is often thought to be permissive, but results from our current grant cycle indicate that IGF-1 has anti-inflammatory, anti-oxidant and anti-atherosclerotic effects. When targeted to smooth muscle cells (SMC), IGF-1 overexpression alters atherosclerotic plaque composition, increasing plaque SMC and collagen content and reducing necrotic cores. These findings suggest that IGF-1 increases plaque stability, which could be very important clinically, since most acute cardiovascular events result from plaque instability, erosion and rupture, rather than changes in plaque burden. The long-term objective of this project is to understand how IGF-1 alters atherosclerotic plaque biology and we will achieve this through two specific aims: Specific Aim 1. Demonstrate that IGF-1-induced atheroprotection is mediated in large part via IGF-1's effect on monocytes/macrophages and investigate mechanisms. We have generated 3 novel mouse models that overexpress IGF-1 constitutively or inducibly in the monocyte/macrophage lineage or in which monocyte/macrophage IGF-1 receptor is deleted. We will use these models to demonstrate that monocyte/macrophage IGF-1 has anti-inflammatory and anti- atherogenic effects and suppresses monocyte chemotaxis, monocyte recruitment and adhesion to endothelium, macrophage lipid accumulation, macrophage oxidative stress/apoptosis, foam cell formation and atherosclerotic plaque development. We will examine mechanisms whereby IGF-1 exerts these effects and in particular the roles of chemokine receptors (CCR1, CCR2) and of 12/15-lipoxygenase and lipoprotein lipase. Specific Aim 2: To demonstrate that IGF-1 increases atherosclerotic plaque stability and determine mechanisms. We will use IGF-1 infusion and SMC targeted IGF-1 transgenic mice and IGF-1 receptor null mice to examine whether effects of IGF-1 on plaque composition, contractile protein and collagen expression are mediated via endocrine and/or autocrine/paracrine mechanisms and whether they translate into a reduced frequency of plaque disruption in the brachiocephalic artery. We will also analyze the role of monocyte/macrophage IGF-1 in these processes. To further understand mechanisms whereby IGF-1 enhances plaque stability we will examine IGF-1 induction of collagen synthesis and assembly in vitro and the involvement of 1221- and 1521-integrins and test potential cross-talk between IGF-1R and 1221 integrin signaling leading to cell cycle suppression and enhanced contractile marker expression. Our results should provide important insights into mechanisms whereby IGF-1, acting on monocytes/macrophages and SMC, alters plaque biology and reduces plaque disruptions. These findings should allow development of innovative therapies targeted at reducing acute vascular events that are most often related to plaque instability.

描述（由申请人提供）：生长因子如胰岛素样生长因子-1（IGF-1）在动脉粥样硬化形成中的作用通常被认为是允许的，但我们当前资助周期的结果表明IGF-1具有抗炎、抗氧化和抗动脉粥样硬化作用。当靶向平滑肌细胞（SMC）时，IGF-1过表达改变动脉粥样硬化斑块的组成，增加斑块SMC和胶原含量，减少坏死核心。这些发现表明，IGF-1增加斑块稳定性，这在临床上可能非常重要，因为大多数急性心血管事件是由斑块不稳定、侵蚀和破裂引起的，而不是斑块负荷的变化。该项目的长期目标是了解IGF-1如何改变动脉粥样硬化斑块生物学，我们将通过两个具体目标实现这一目标：具体目标1。证明IGF-1诱导的动脉粥样硬化保护作用在很大程度上是通过IGF-1对单核细胞/巨噬细胞的作用介导的，并研究其机制。我们已经产生了3种新的小鼠模型，它们在单核细胞/巨噬细胞谱系中组成性或诱导性地过表达IGF-1，或者其中单核细胞/巨噬细胞IGF-1受体缺失。我们将使用这些模型来证明单核细胞/巨噬细胞IGF-1具有抗炎和抗动脉粥样硬化作用，并抑制单核细胞趋化性、单核细胞募集和粘附至内皮、巨噬细胞脂质积聚、巨噬细胞氧化应激/凋亡、泡沫细胞形成和动脉粥样硬化斑块发展。我们将研究IGF-1发挥这些作用的机制，特别是趋化因子受体（CCR 1，CCR 2）和12/15-脂氧合酶和脂蛋白脂肪酶的作用。具体目标2：证明IGF-1增加动脉粥样硬化斑块稳定性并确定机制。我们将使用IGF-1输注和SMC靶向IGF-1转基因小鼠和IGF-1受体缺失小鼠来检查IGF-1对斑块组成、收缩蛋白和胶原表达的影响是否通过内分泌和/或自分泌/旁分泌机制介导，以及它们是否转化为头臂动脉中斑块破裂频率的降低。我们还将分析单核细胞/巨噬细胞IGF-1在这些过程中的作用。为了进一步了解IGF-1增强斑块稳定性的机制，我们将检查IGF-1对体外胶原合成和组装的诱导以及1221和1521整联蛋白的参与，并测试IGF-1 R和1221整联蛋白信号传导之间潜在的串扰，导致细胞周期抑制和增强收缩标志物表达。我们的研究结果应提供重要的见解IGF-1，作用于单核细胞/巨噬细胞和SMC，改变斑块生物学和减少斑块破坏的机制。这些发现应该允许开发针对减少最常与斑块不稳定相关的急性血管事件的创新疗法。