title: Repression of P66Shc expression by SIRT1 contributes to the prevention of hyperglycemia-induced endothelial dysfunction.
abstract: BACKGROUND
  Inactivation of the p66Shc adaptor protein confers resistance to oxidative stress and protects mice from aging-associated vascular diseases. However, there is limited information about the negative regulating mechanisms of p66Shc expression in the vascular system.
  
  
  OBJECTIVE
  In this study, we investigated the role of SIRT1, a class III histone deacetylase, in the regulation of p66Shc expression and hyperglycemia-induced endothelial dysfunction.
  
  
  RESULTS
  Expressions of p66Shc gene transcript and protein were significantly increased by different kinds of class III histone deacetylase (sirtuin) inhibitors in human umbilical vein endothelial cells and 293A cells. Adenoviral overexpression of SIRT1 inhibited high-glucose-induced p66Shc upregulation in human umbilical vein endothelial cells. Knockdown of SIRT1 increased p66Shc expression and also increased the expression levels of plasminogen activator inhibitor-1 expression, but decreased manganese superoxide dismutase expression in high-glucose conditions. However, knockdown of p66Shc significantly reversed the effects of SIRT1 knockdown. In addition, p66Shc overexpression significantly decreased manganese superoxide dismutase expression and increased plasminogen activator inhibitor-1 expression in high-glucose conditions, which were recovered by SIRT1 overexpression. Moreover, compared to streptozotocin-induced wild-type diabetic mice, endothelium-specific SIRT1 transgenic diabetic mice had decreased p66Shc expression at both the mRNA and the protein levels, improved endothelial function, and reduced accumulation of nitrotyrosine and 8-OHdG (markers of oxidative stress). We further found that SIRT1 was able to bind to the p66Shc promoter (-508 bp to -250 bp), resulting in a decrease in the acetylation of histone H3 bound to the p66Shc promoter region.
  
  
  CONCLUSIONS
  Our findings indicate that repression of p66Shc expression by SIRT1 contributes to the protection of hyperglycemia-induced endothelial dysfunction.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.forename: Yan-Zhen
authors.initials: YZ
authors.lastname: Wan
authors.forename: Qing-Jun
authors.initials: QJ
authors.lastname: Zhang
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Wei
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Liu
authors.forename: Yun-Biao
authors.initials: YB
authors.lastname: Lu
authors.forename: Zhu-Qin
authors.initials: ZQ
authors.lastname: Zhang
authors.forename: Rui-Feng
authors.initials: RF
authors.lastname: Yang
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
authors.forename: Chih-Chuan
authors.initials: CC
authors.lastname: Liang
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D007113:Immunity, Innate / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics; D055550:Protein Stability; D055765:Shc Signaling Adaptor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D056564:Sirtuin 1 / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C447939:SIRT1 protein, human; D056564:Sirtuin 1