Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells

Hidetaka Ota, Masato Eto, Mitsunobu R. Kano, Sumito Ogawa, Katsuya Iijima, Masahiro Akishita, Yasuyoshi Ouchi

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

OBJECTIVE-: Cilostazol, a selective inhibitor of PDE3, has a protective effect on endothelium after ischemic vascular damage, through production of nitric oxide (NO). The purpose of the present study was to clarify the molecular mechanisms underlying the preventive effect of treatment with cilostazol on oxidative stress-induced premature senescence in human endothelial cells. METHODS AND RESULTS-: Prematurely senescent human umbilical vein endothelial cells (HUVECs) were induced by treatment with hydrogen peroxide (H2O2) as judged by senescence-associated β-galactosidase assay (SA-βgal), cell morphological appearance, and plasminogen activator inhibitor-1 (PAI-1) expression. Treatment with H2O2 caused 93% of the cells to be SA-βgal positive, whereas 46% of cilostazol (100 μmol/L)-treated cells were positive. HUVECs treated with other cAMP-elevating agents and DETA-NO showed a reduction of SA-βgal-positive cells as well. Cilostazol increased phosphorylation of Akt at Ser and of endothelial nitric oxide synthase (eNOS) at Ser, with a dose-dependent increase in Sirt1 expression. Moreover, the effect of cilostazol on premature senescence was abrogated through inhibition of Sirt1. CONCLUSIONS-: Our results indicated that cilostazol exerted protective effects against endothelial senescence and dysfunction, and enhancement of NO production is a key mediator in upregulation of Sirt1.

Original languageEnglish
Pages (from-to)1634-1639
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number9
DOIs
Publication statusPublished - Sep 1 2008
Externally publishedYes

Keywords

  • Cilostazol
  • Endothelial senescence
  • Sirt1
  • eNOS

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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