Cell Signaling: Macrovascular Complications of Diabetes

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DESCRIPTION (provided by applicant): A majority of people with diabetes die of cardiovascular disease caused by atherosclerosis that is accelerated by diabetes. The factors that drive diabetes-accelerated atherosclerosis are still poorly understood. Our recent studies on a new porcine model show that diabetes in combination with elevated lipid intake causes increased accumulation and proliferation of arterial smooth muscle cells (SMCs) in lesions of atherosclerosis. The increased SMC proliferation occurs concomitant with hyperglycemia and elevated levels of plasma triglycerides. High glucose levels are not sufficient to induce SMC proliferation, but certain fatty acids common in triglycerides (oleate and linoleate) stimulate SMC proliferation in the presence of insulin-like growth factor I (IGF-I). We propose that diabetes leads to an increased amount of IGF-I and of lipoprotein lipase in lesion macrophages, and that lipoprotein lipase degrades triglycerides into free fatty acids that act in synergy with IGF-I to stimulate SMC proliferation. Our goal for the next five years is to address the following questions: 1. Do oleate and linoleate enhance the growth-promoting effects of IGF-I on SMCs? 2. How do oleate and linoleate synergize with the growth-promoting action of IGF-I in SMCs? 3. Does lipoprotein lipase produced by lipid loaded macrophages increase SMC proliferation by generating oleate and linoleate? 4. Does glucose or lipids associated with diabetes stimulate SMC proliferation, lipoprotein lipase and IGF-I in lesions of atherosclerosis and does lack of macrophage-derived lipoprotein lipase result in reduced SMC proliferation? We will use several animal models of diabetes-associated atherosclerosis, isolated arterial SMCs for signal transduction studies as well as a co-culture model of monocyte derived macrophages and SMCs. Increased understanding of the regulation of SMC proliferation and accumulation in diabetic lesions of atherosclerosis may provide the basis information necessary for development of highly specific drugs that can prevent lesion progression and formation of vulnerable lesions that are likely to cause the clinical symptoms of cardiovascular complications in diabetes.