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Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1-mediated p53/KLF4 complex stabilization.
Xi, Gang; Shen, Xinchun; Wai, Christine; White, Morris F; Clemmons, David R.
Affiliation
  • Xi G; From the Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
  • Shen X; the College of Food Science and Engineering, Nanjing University of Finance and Economics, Nanjing 210023, China, and.
  • Wai C; From the Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599.
  • White MF; the Division of Endocrinology, Department of Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
  • Clemmons DR; From the Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, david_clemmons@med.unc.edu.
J Biol Chem ; 294(7): 2407-2421, 2019 02 15.
Article in En | MEDLINE | ID: mdl-30578299
Hyperglycemia and insulin resistance accelerate atherosclerosis by an unclear mechanism. The two factors down-regulate insulin receptor substrate-1 (IRS-1), an intermediary of the insulin/IGF-I signaling system. We previously reported that IRS-1 down-regulation leads to vascular smooth muscle cell (VSMC) dedifferentiation and that IRS-1 deletion from VSMCs in normoglycemic mice replicates this response. However, we did not determine IRS-1's role in mediating differentiation. Here, we sought to define the mechanism by which IRS-1 maintains VSMC differentiation. High glucose or IRS-1 knockdown decreased p53 levels by enhancing MDM2 proto-oncogene (MDM2)-mediated ubiquitination, resulting in decreased binding of p53 to Krüppel-like factor 4 (KLF4). Exposure to nutlin-3, which dissociates MDM2/p53, decreased p53 ubiquitination and enhanced the p53/KLF4 association and differentiation marker protein expression. IRS-1 overexpression in high glucose inhibited the MDM2/p53 association, leading to increased p53 and p53/KLF4 levels, thereby increasing differentiation. Nutlin-3 treatment of diabetic or Irs1-/- mice enhanced p53/KLF4 and the expression of p21, smooth muscle protein 22 (SM22), and myocardin and inhibited aortic VSMC proliferation. Injecting normoglycemic mice with a peptide disrupting the IRS-1/p53 association reduced p53, p53/KLF4, and differentiation. Analyzing atherosclerotic lesions in hypercholesterolemic, diabetic pigs, we found that p53, IRS-1, SM22, myocardin, and KLF4/p53 levels are significantly decreased compared with their expression in nondiabetic pigs. We conclude that IRS-1 is critical for maintaining VSMC differentiation. Hyperglycemia- or insulin resistance-induced IRS-1 down-regulation decreases the p53/KLF4 association and enhances dedifferentiation and proliferation. Our results suggest that enhancing IRS-1-dependent p53 stabilization could attenuate the progression of atherosclerotic lesions in hyperglycemia and insulin-resistance states.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cell Differentiation / Tumor Suppressor Protein p53 / Myocytes, Smooth Muscle / Multiprotein Complexes / Kruppel-Like Transcription Factors / Insulin Receptor Substrate Proteins / Hyperglycemia / Muscle, Smooth, Vascular Limits: Animals / Humans Language: En Journal: J Biol Chem Year: 2019 Document type: Article Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cell Differentiation / Tumor Suppressor Protein p53 / Myocytes, Smooth Muscle / Multiprotein Complexes / Kruppel-Like Transcription Factors / Insulin Receptor Substrate Proteins / Hyperglycemia / Muscle, Smooth, Vascular Limits: Animals / Humans Language: En Journal: J Biol Chem Year: 2019 Document type: Article Country of publication: