Down regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation*
Diabetes is a major risk factor for the development of atherosclerosis, but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulin like growth factor I (IGF I) signal through the scaffold protein insulin receptor substrate 1 (IRS 1) In diabetes, IRS 1 is down regulated, and cells become resistant to insulin. Under these conditions, the IGF I receptor signals through an alternate scaffold protein, SHPS 1, resulting in pathophysiologic stimulation of vascular smooth muscle cell (VSMC) migration and proliferation. These studies were undertaken to determine whether IRS 1 is functioning constitutively to maintain VSMCs in their differentiated state and, thereby, inhibit aberrant signaling. Here we show that deletion of IRS 1 expression in VSMCs in non diabetic mice results in dedifferentiation, SHPS 1 activation, and aberrant signaling and that these changes parallel those that occur in response to hyperglycemia. The mice showed enhanced sensitivity to IGF I stimulation of VSMC proliferation and a hyperproliferative response to vascular injury. KLF4, a transcription factor that induces VSMC dedifferentiation, was up regulated in IRS 1 mice, and the differentiation inducer myocardin was undetectable. Importantly, these changes were replicated in wild type mice during hyperglycemia. These findings illuminate a new function of IRS 1: that of maintaining cells in their normal, differentiated state. Because IRS 1 is down regulated in states of insulin resistance that occur in response to metabolic stresses such as obesity and cytokine stimulation, the findings provide a mechanism for understanding how patients with metabolic stress and/or diabetes are predisposed to developing vascular complications.
The Journal of Biological Chemistry