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.
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