456-P: Targeted Deletion of Insulin Receptor in Vascular Smooth Muscle Cells Accelerated Thinning of Plaque Cap and Apoptosis and Atherosclerosis

Vascular smooth muscle cells (VSMCs) play an important role in the development of the stability of atherosclerotic plaque. We reported that knockout of insulin receptor (IR), but not IGF1 receptor, in VSMCs reduced intimal hyperplasia of femoral artery after wire injury. To investigate the role of IR in VSMCs on atherosclerotic plaque, ApoE and smooth muscle cells IR double knockout (SMIRKO/ApoE^-/-) mice were generated. Extent of lipid deposition and atherosclerosis were increased in the aorta of SMIRKO/ApoE^-/- mice compared to control mice (p<0.05). However, total cell numbers and proliferation of VSMCs, cap thickness and collagen of the plaque were decreased, whereas VSMCs apoptosis, macrophage content and necrotic area were increased in the aortic plaques of SMIRKO/ApoE^-/- mice compared to ApoE^-/- mice. VSMCs cultured from SMIRKO/ApoE^-/- mice exhibited more apoptosis by withdrawing growth factors which were inhibited by insulin compared to VSMCs from ApoE^-/- mice. Analysis of genes in VSMCs subsets which were reported to be increased in aortic plaques showed MMP2, decorin, thrombospondin 1 and 5, sFRP3 and IGFBP4 were increased in the aortic media of SMIRKO/ApoE^-/- mice vs. ApoE^-/- mice, with MMP2, thrombospondin 1 and 5 and sFRP3 were also increased in the aortic media of mice fed with high fat diet or diabetic mice due to streptozotocin injection. Insulin downregulated MMP2 and thrombospondin 1 in cultured VSMCs, whereas overexpression of Foxo1 in VSMCs increased the expression of thrombospondin 1. Reanalysis of existed microarray data base and found MMP2 and thrombospondin 1 were also elevated in internal mammary artery of diabetic compared to nondiabetic people. Thus, insulin receptor action on VSMCs can change expression of extracellular genes and its turnover to increase the stability of atherosclerotic plaque.