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.
Most acute cardiovascular events such as heart attacks are caused by disruption of atherosclerotic plaques which have become unstable. We propose to use a growth factor called IGF-1 to reduce the size and alter the composition of these plaques in animals, making them less inflammatory and more stable. If applied to humans this strategy could be a breakthrough that reduces the incidence of acute cardiovascular events.
|Sakamuri, Siva Sankara Vara Prasad; Higashi, Yusuke; Sukhanov, Sergiy et al. (2016) TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE(-/-) mice. Atherosclerosis 252:153-60|
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|Higashi, Yusuke; Sukhanov, Sergiy; Shai, Shaw-Yung et al. (2016) Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice. Circulation 133:2263-78|
|Sukhanov, Sergiy; Snarski, Patricia; Vaughn, Charlotte et al. (2015) Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase. Atherosclerosis 238:313-20|
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|Blackstock, Christopher D; Higashi, Yusuke; Sukhanov, Sergiy et al. (2014) Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5' stem-loop of COL1a1 and COL1a2 mRNA. J Biol Chem 289:7264-74|
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|Xing, S S; Shen, C C; Godard, M P et al. (2014) Bortezomib inhibits C2C12 growth by inducing cell cycle arrest and apoptosis. Biochem Biophys Res Commun 445:375-80|
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