Vascular smooth muscle cell (VSMC) growth is a critical step in the development of restenosis and is likely an important contributor to the pathogenesis of atherosclerosis, although its role in the latter needs to be established. The objective of this proposal will be to systematically define and compare the effects of insulin resistance, hyperinsulinemia, diabetes, and angiotensin II on the development of both intimal hyperplasia (balloon angioplasty in the rat) and VSMC growth in atherosclerosis (LDL receptor knockout mouse). An exciting aspect of this investigation is that we will use thiazolidinedione analogs to alter these pathologies, since we have discovered that they inhibit VSMC growth in addition to their well- known activity to enhance insulin mediated glucose uptake. This action may be due to the ability of these agents to inhibit nuclear translocation of mitogen activated protein (MAP) kinase which we will investigate. We further demonstrated that this growth inhibitory effect is relevant in vivo, since troglitazone, a member of the thiazolidinedione family, inhibited VSMC intimal hyperplasia in the rat aortic injury model. These novel analogs will now allow us to elucidate the importance of VSMC growth ina the atherosclerotic process and the critical cellular signal transduction mechanisms mediating growth in VSMC.
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