Diabetes is lethal. Most people with diabetes will die prematurely of vascular disease. Our long term objective is to clarify the mechanisms underlying atherosclerosis in diabetes. Type 2 diabetes is an especially important public health problem characterized by abnormal fatty acid metabolism in addition to hyperglycemia. Abnormal fatty acid metabolism precedes hyperglycemia during the progression from insulin resistance to beta cell failure in type 2 patients, suggesting that fatty acids may contribute to the high rate of vascular disease seen in such patients at the time of diagnosis. The experiments in this application will test the hypothesis that fatty acid metabolism in the vessel wall promotes atherosclerosis in part through effects on expression of the alpha-v beta3 integrin. We will pursue four specific aims, all involving apolipoprotein E null mice: 1) To determine if overexpression of lipoprotein lipase enzyme activity in vascular smooth muscle cells affects atherosclerosis and alpha-v beta3 integrin expression. 2) To determine if overexpression of PPARalpha in vascular smooth muscle cells or endothelium affects atherosclerosis and alpha-v beta3 integrin expression. 3) To determine if overexpression of the beta3 integrin subunit in vascular smooth muscle cells or endothelium affects atherosclerosis. 4) To determine if tissue-specific PPARalpha deficiency (achieved with Cre-loxP technology) in the vessel wall affects atherosclerosis and alpha-v beta3 integrin expression. This project has the potential to prove the concept that altering fatty acid metabolism in the native cells of the artery wall affects atherosclerosis. These experiments could lead to innovative strategies for the treatment of vascular disease in diabetes.
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