Down-regulation of insulin receptor substrate 1 during hyperglycemia induces vascular smooth muscle cell dedifferentiation

Gang Xi, Christine Wai, Morris F. White, David R. Clemmons

Research output: Contribution to journalArticle

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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 insulinlike growth factor I (IGF-I) signal through the scaffold protein insulin receptor substrate 1 (IRS-1). In diabetes, IRS-1 is downregulated, 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 nondiabetic mice results in dedifferentiation, SHPS-1 activation, and aberrant signaling and that these changes parallel those that occur inresponsetohyperglycemia.Themiceshowedenhancedsensitivity 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, differentiatedstate. BecauseIRS-1isdown-regulatedinstatesofinsulinresistance 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.

LanguageEnglish (US)
Pages2009-2020
Number of pages12
JournalJournal of Biological Chemistry
Volume292
Issue number5
DOIs
StatePublished - Feb 3 2017

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Cell Dedifferentiation
Insulin Receptor Substrate Proteins
Vascular Smooth Muscle
Hyperglycemia
Smooth Muscle Myocytes
Muscle
Down-Regulation
Cells
Medical problems
Intercellular Signaling Peptides and Proteins
Physiological Stress
Scaffolds
Cell Proliferation
Insulin
Growth Factor Receptors
Vascular System Injuries
Cell proliferation
Cell Movement
Blood Vessels
Atherosclerosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Down-regulation of insulin receptor substrate 1 during hyperglycemia induces vascular smooth muscle cell dedifferentiation. / Xi, Gang; Wai, Christine; White, Morris F.; Clemmons, David R.

In: Journal of Biological Chemistry, Vol. 292, No. 5, 03.02.2017, p. 2009-2020.

Research output: Contribution to journalArticle

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