40-OR: Insulin Stabilized Arterial Plaque by Regulating Vascular Smooth Muscle Cell Metabolism and Differentiation

The main pathology of cardiovascular diseases (CVD) in insulin resistance and diabetes is an acceleration of atherosclerosis and increased risk for the development of unstable plaques. Insulin’s effect on vascular smooth muscle cell (VSMC) has been attributed to be pro-atherogenic due to its actions to increase migration and proliferation. We reported that insulin receptors (IR) are responsible for increasing arterial intimal hyperplasia after wire injury. Surprisingly, mice with VSMC specific deletion of IR (Myh11IRKO/ApoE^-/-), atherosclerosis was increased with plaques exhibited unstable pathologies of less VSMC and ECM, but more macrophages and necrosis than ApoE^-/- mice. To characterize these unexpected findings in the arterial plaques of Myh11IRKO/ApoE^-/- mice, we performed single cell RNA sequencing study of VSMC comparing 4 groups of mice including ApoE^-/- and MyH11IRKO/ApoE^-/- on normal chow or high fat diet (HFD). Bioinformatics analysis demonstrated that VSMC can be separated into 21 distinctive clusters with those expression enriched for contractile and mitochondrial genes separated from clusters which expressed heat shock protein (HSP) or inflammatory genes. Aorta of HFD insulin resistant WT ApoE^-/- mice exhibited significantly increases of multiple clusters of inflammatory VSMCs and, surprisingly, also those clusters enriched for mitochondrial metabolism. However, in Myh11IRKO/ApoE^-/- mice on HFD, aortic VMSC clusters with contractile and mitochondrial genes were significantly reduced, but distinct VMSC clusters with expressions of HSP or inflammatory genes were greatly increased. These novel findings, along with metabolic studies in cultured VSMC, indicated that insulin’s actions on VSMC metabolism to reduce the transition of VSMCs subsets from mitochondria enriched VSMCs to stressed and inflammatory VSMCs, which is critical to increase plaque stability and decrease CVD risks in people with insulin resistance and diabetes.