Sirt1 modulates premature senescence-like phenotype in human endothelial cells

J Mol Cell Cardiol. 2007 Nov;43(5):571-9. doi: 10.1016/j.yjmcc.2007.08.008. Epub 2007 Aug 22.


Yeast Sir2 plays critical roles in gene silencing, stress resistance and longevity. Mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homolog of Sir2, regulates cell cycle, cellular senescence, apoptosis and metabolism, by functional interactions with a number of biological molecules such as p53. To investigate a role of Sirt1 in endothelial dysfunction and premature senescence, we examined the effects of Sirt1 inhibition in human umbilical vein endothelial cells (HUVEC). Sirt1 inhibition by sirtinol, which is a 2-hydroxy-1-napthaldehyde derivative, or siRNA for Sirt1-induced premature senescence-like phenotype, as judged by increased senescence-associated beta-galactosidase (SA-beta-gal) activity, sustained growth arrest and enlarged and flattened cell morphology at 10 days after the treatment. Sixty-four percent of sirtinol (60 mumol/L)-treated HUVEC was SA-beta-gal-positive, whereas only 17% of vehicle-treated cells were positive. Sirt1 inhibition by sirtinol or Sirt1 siRNA increased PAI-1 expression and decreased both protein expression and activity of eNOS. Treatment with sirtinol or Sirt1 siRNA increased acetylation of p53, while p53 expression was unaltered. Impaired epidermal growth factor-induced activation of mitogen-activated protein kinases was associated with Sirt1 inhibition-induced senescence-like growth arrest. Conversely, overexpression of Sirt1 prevented hydrogen peroxide-induced SA-beta-gal activity, morphological changes and deranged expression of PAI-1 and eNOS. These results showed that Sirt1 inhibition increased p53 acetylation and induced premature senescence-like phenotype in parallel with increased PAI-1 and decreased eNOS expression. Our data suggest that Sirt1 may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence and deranged expression of PAI-1 and eNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division / physiology
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / physiology*
  • Humans
  • Nitric Oxide Synthase / metabolism
  • Phenotype
  • RNA, Small Interfering / genetics
  • Recombinant Proteins / metabolism
  • Sirtuin 1
  • Sirtuins / antagonists & inhibitors
  • Sirtuins / genetics
  • Sirtuins / physiology*
  • Transfection
  • Umbilical Veins
  • beta-Galactosidase / metabolism


  • RNA, Small Interfering
  • Recombinant Proteins
  • Nitric Oxide Synthase
  • beta-Galactosidase
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins