title: Protective role of SIRT1 in diabetic vascular dysfunction.
abstract: OBJECTIVE
  Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD(+)-dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood.
  
  
  RESULTS
  Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes.
  
  
  CONCLUSIONS
  These findings represent a novel mechanism of vascular cell senescence induced by hyperglycemia and suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Orimo
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Miyauchi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tateno
authors.forename: Sho
authors.initials: S
authors.lastname: Okada
authors.forename: Junji
authors.initials: J
authors.lastname: Moriya
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000107:Acetylation; D000818:Animals; D001011:Aorta / Q000201:enzymology; D002478:Cells, Cultured; D016922:Cellular Senescence; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D020536:Enzyme Activators / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction; D056564:Sirtuin 1; D037761:Sirtuins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D051858:Forkhead Transcription Factors; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D005947:Glucose; D000077185:Resveratrol