Insulin-like Growth Factor-1 and Atherosclerosis

描述(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，但我们目前的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的作用。当以平滑肌细胞(SMC)为靶点时，IGF-1的过表达改变了动脉粥样硬化斑块的组成，增加了斑块SMC和胶原的含量，并减少了坏死灶。这些发现表明，IGF-1增加了斑块的稳定性，这在临床上可能是非常重要的，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。本项目的长期目标是了解胰岛素样生长因子-1是如何改变动脉粥样硬化斑块生物学的，我们将通过两个特定的目标来实现这一点：具体目的1.证明胰岛素样生长因子-1诱导的动脉粥样硬化保护作用在很大程度上是通过胰岛素样生长因子-1的S作用于单核/巨噬细胞而实现的，并探讨其机制。我们已经建立了3种新的小鼠模型，这些模型在单核/巨噬细胞系中结构性或诱导性地过度表达IGF-1，或者在其中单核/巨噬细胞IGF-1受体缺失。我们将使用这些模型来证明单核/巨噬细胞IGF-1具有抗炎和抗动脉粥样硬化的作用，并抑制单核细胞趋化、单核细胞募集和与内皮的黏附、巨噬细胞脂质堆积、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的形成。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(CCR1、CCR2)以及12/15-脂氧合酶和脂蛋白脂肪酶的作用。具体目的2：证明IGF-1增加动脉粥样硬化斑块的稳定性并确定其作用机制。我们将使用IGF-1输注和SMC靶向IGF-1转基因小鼠和IGF-1受体缺失小鼠来研究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减少头臂动脉斑块破裂的频率。我们还将分析单核/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，我们将研究IGF-1对体外胶原合成和组装的诱导以及1221和1521整合素的参与，并测试IGF-1R和1221整合素信号之间的潜在串扰，导致细胞周期抑制和收缩标记表达增强。我们的结果应该为IGF-1作用于单核/巨噬细胞和SMC改变斑块生物学和减少斑块破坏的机制提供重要的见解。这些发现将有助于开发旨在减少急性血管事件的创新疗法，急性血管事件最常与斑块不稳定性有关。

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.