title: Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation.
abstract: 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.
authors.affiliation: From the Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Gang
authors.initials: G
authors.lastname: Xi
authors.affiliation: From the Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
authors.forename: Christine
authors.initials: C
authors.lastname: Wai
authors.affiliation: the Division of Endocrinology, Department of Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.affiliation: From the Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599. Electronic address: david_clemmons@med.unc.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Clemmons
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D015536:Down-Regulation; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic
keywords: atherosclerosis; diabetes; insulin receptor substrate 1 (IRS-1); insulin resistance; myocardin; vascular smooth muscle cells