1482-PUB: Insulin Receptors in Vascular Smooth Muscle Cells Regulate Plaque Stability by Its actions on Glycolysis and Oxidative Phosphorylation

Vascular smooth muscle cells (VSMC) have prominent roles in the pathology of atherosclerotic plaque, where it forms intimal hyperplasia, maintains extracellular matrix (ECM) and interacts with lipoproteins to accelerate inflammation and formation of foam cells. Diabetes and insulin resistance exacerbate all of these histopathologies of atherosclerotic plaques. Further, diabetes increase the formation of unstable plaques that feature less VSMC and ECM, but more inflammatory cells and necrotic lesions, which, on rupture, cause thrombosis and acute myocardial infarction. We reported that insulin receptors (IR) are responsible for increasing arterial restenosis since mouse with IR deletion in the VSMC showed less proliferation, more apoptosis, and less arterial hyperplasia after intimal injury. Surprisingly, in mice with specific deletion of IR in VSMC (SMIRKO/ApoE^-/-) , severity of atherosclerosis was increased and the plaques exhibited unstable pathologies of less VSMC and ECM, but greater levels of macrophages and necrosis than ApoE^-/- mice. Analysis of glucose glycolysis (extracellular acidification rate, ECAR) and oxidative phosphorylation (oxygen consumption rate, OCR) , using Seahorse assay, showed dramatically decreased metabolic rates in VSMC from SMIRKO/ApoE^-/- compared to ApoE-/- mice. Overexpression of IR in VSMCs increased ECAR and OCR, which were further stimulate by insulin, only in VSMC with IR. [J1] Insulin increased expressions of glycolytic enzymes including hexokinase 2 and phopshofructose kinase in VSMCs overexpressing IR. These findings have identified the importance of IR on the regulation of glycolysis and mitochondrial metabolism in VSMC, which could increase the stability of the atherosclerotic plaques by increased VSMCs proliferation and ECM, but reduced their apoptosis and productions of inflammatory cytokines. [J1]Hard to understand⋯maybe combine with the next phrase?