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Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial

Shuang Zhou1, Hou-Zao Chen, Yan-Zhen Wan

  • 1National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.

Circulation Research
|July 23, 2011
PubMed
Abstract

Insights

SIRT1 represses p66Shc expression, protecting against high-glucose-induced endothelial dysfunction. This finding reveals a key mechanism in vascular aging and diabetes complications.

Area of Science:

  • Vascular Biology
  • Epigenetics
  • Metabolic Disease

Background:

  • p66Shc adaptor protein inactivation confers oxidative stress resistance and protects against aging-associated vascular diseases.
  • Limited information exists on negative regulatory mechanisms of p66Shc expression in the vascular system.

Purpose of the Study:

  • Investigate the role of SIRT1 (a class III histone deacetylase) in regulating p66Shc expression.
  • Determine SIRT1's role in hyperglycemia-induced endothelial dysfunction.

Main Methods:

  • Utilized human umbilical vein endothelial cells and 293A cells treated with sirtuin inhibitors.
  • Employed adenoviral overexpression and knockdown techniques for SIRT1 and p66Shc.
  • Analyzed gene and protein expression, endothelial function, and oxidative stress markers in diabetic mouse models.

Main Results:

  • Sirtuin inhibitors increased p66Shc expression; SIRT1 overexpression inhibited high-glucose-induced p66Shc upregulation.
  • SIRT1 knockdown increased p66Shc, plasminogen activator inhibitor-1, and decreased manganese superoxide dismutase; p66Shc knockdown reversed these effects.
  • Endothelium-specific SIRT1 transgenic diabetic mice showed decreased p66Shc, improved endothelial function, and reduced oxidative stress markers compared to wild-type diabetic mice.
  • SIRT1 binds to the p66Shc promoter, decreasing histone H3 acetylation.

Conclusions:

  • SIRT1 represses p66Shc expression, contributing to the protection against hyperglycemia-induced endothelial dysfunction.
  • This study elucidates a novel epigenetic mechanism involving SIRT1 and p66Shc in vascular health under diabetic conditions.

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