EXCEED THE SPACE PROVIDED. The clinical sequelae of atherosclerosis are broad and result in cardiovascular disease being the leading cause of mortality in the Western world. Acute manifestations of atherosclerosis result in most instances from plaque rupture. Mechanisms leading to plaque rupture include increased inflammation, particularly in the shoulder area of the plaque, and depletion of vascular smooth muscle cells (VSMC) resulting in fibrous cap thinning. Oxidized LDL (OxLDL) plays an important role in all stages of atherosclerosis, and is a primary trigger for foam cell accumulation, and apoptosis of macrophages, endothelial cells and VSMC. Insulin-like Growth Factor-1 (IGF-1) is a potent survival factor for many cells including VSMC. In vitro, OxLDL decreases IGF-1 and IGF-1 receptor (IGF-1 R) expression. The long-term goal of this project is to determine the role of the IGF- 1 system in the ability of OxLDL to trigger VSMC apoptosis and accelerate atherosclerotic lesion development.
Specific aims are: 1. Study the effect of OxLDL on the IGF-1R survival pathway in VSMC. 2. Study the effect of VSMC-targeted deletion of the IGF-1R on atherosclerotic lesion formation in ApoE knockout mice. 3. Study the effect of VSMC-targeted overexpression of the IGF-1R on atherosclerotic lesion formation in ApoE-/-(knockout) mice. The primary focus of this proposal will be to determine if IGF-1 acting through it's IGF-1R can rescue cells from OxLDL induced apoptosis. These studies will provide important new information regarding mechanisms of apoptosis in human arterial smooth muscle cells, offering new therapeutic targets for the prevention of acute cardiovascular events. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070241-03
Application #
6829098
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Tolunay, Eser
Project Start
2002-12-05
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2005
Total Cost
$371,250
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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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
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