Loss Of Insulin‐like Growth Factor 1 Receptor In Vascular Smooth Muscle Cells Promotes Increased Mirna‐221 And ‐222 In Type 2 Diabetes

Abstract

Type 2 diabetes mellitus is associated with a 2 to 4 times higher risk of a heart attack or stroke. This increased risk of heart attacks and strokes results from an accelerated development of atherosclerotic plaques. During atherosclerotic plaque development, vascular smooth muscle cells (VSMC) proliferate and migrate leading to thickening of the intima of the arterial walls. This process is accelerated in diabetic patients by increase in two miRNAs, miR-221 and -222. These miRNAs are sensitive to changes in insulin receptor (IR) signaling. Under normal conditions, most of IR subunits are bound to insulin-like growth factor-1 receptor (IGFR) subunits forming heterodimers, which largely function as IGFR homodimers. A loss of IGFR thus promotes increased IR homodimers and an increase in insulin signaling. Our objective is to evaluate the effect of loss of IGFR on miR-221 and -222 expression in VSMCs. We hypothesize that the loss of IGFR coupled with physiological insulin stimulation promotes increased expression of miR-221/-222, which will in turn promote increased VSMC proliferation and migration. IGFR expression was measured in human atherosclerotic plaque samples from diabetic patients and nondiabetic patients. The effects of insulin stimulation coupled with the absence of IGFR was modeled with VSMCs isolated from an VSMC-specific IGFR knockout mouse. Our data demonstrates that arteries from diabetic subjects exhibit a 5.5-fold loss of the insulin-like growth factor receptor (IGFR-1). Murine vascular smooth muscle cells lacking IGFR exhibit a dose-dependent increase in miR-221/222 in response to physiological insulin stimulation. We conclude that loss of IGFR, likely increasing IR holoreceptors, alters insulin signaling to promote increased miR-221/222 in response to physiological insulin. These data provide support for the loss of IGFR as an initiator of the increase in intimal thickening seen in type 2 diabetes associated with miR-221/222.