54-OR: Insulin Stabilized Arterial Plaques by Regulating Vascular Smooth Muscle Differentiation

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Introduction and Objective: Risk of unstable plaques, noted by reduced content of vascular smooth muscle cells (VSMC) and extracellular matrix (ECM), with elevated inflammatory cells and necrosis, are increased in diabetes for unknown reasons. This study investigated the role of insulin in VSMC and the formation of unstable plaques.Methods: Insulin receptor (IR) knockout and VSMC lineage tracing mice (MyH11IRKO/ApoE-/-) were generated. Single cell RNA sequencing (scRNA Seq) was performed with isolated VSMC from control and MyH11IRKO/ApoE-/- mice on normal (ND) or high fat diet (HFD). Changes observed in mice were validated in arteries from subjects with and without Type 2 diabetes (T2D) by immunostaining.Results: Atherosclerotic plaques in MyH11IRKO/ApoE-/- mice were increased and exhibited unstable traits with reductions of VSMC and ECM, but greater numbers of macrophages and necrosis than ApoE-/- mice. ScRNA Seq analysis of aortae identified 21 distinctive clusters of VSMC, which are separated into clusters with enriched expressions of contractile, ribosome and mitochondrial genes to those expressing inflammatory genes. Both inflammatory VSMCs clusters and those enriched for ribosomal and mitochondrial genes were increased in HFD fed ApoE-/- mice vs. those on ND. However, in Myh11IRKO/ApoE-/- mice on HFD, VSMC enriched for ribosomal and mitochondrial genes were significantly reduced, but VSMC expressing elevated inflammatory cytokines and matrix metalloproteinases (MMP’s) were increased vs.HFD fed ApoE-/- mice. These changes of reductions of VSMC with ribosomal proteins and elevations of VSMC with inflammatory cytokines and MMPs were validated in arteries from people with diabetes.Conclusion: scRNA seq analysis showed that insulin actions are critical to prevent the differentiation of VSMC into clusters expressing inflammatory cytokines and MMPs, which are critical for the pathogenesis of unstable arterial plaques associated with insulin resistance and T2D.

Disclosure

Q. Li: None. J. Fu: None. K. Park: None. M. Yu: None. G.L. King: None.



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