on June 12, 2008
Published online before print June 12, 2008, doi: 10.1161/ATVBAHA.108.164368
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Submitted on February 4, 2008
Accepted on May 28, 2008
Cilostazol Inhibits Oxidative Stress–Induced Premature Senescence via Upregulation of Sirt1 in Human Endothelial Cells
Hidetaka Ota ;
From the Departments of Geriatric Medicine (H.O., M.E., S.O., K.I., M.A., Y.O.), and Molecular Pathology (M.R.K.), Graduate School of Medicine, University of Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: youchi-tky{at}umin.ac.jp.
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 
-galactosidase assay (SA-gal), cell morphological appearance, and plasminogen activator inhibitor-1 (PAI-1) expression. Treatment with H2O2 caused 93% of the cells to be SA-gal 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-gal–positive cells as well. Cilostazol increased phosphorylation of Akt at Ser473 and of endothelial nitric oxide synthase (eNOS) at Ser1177, 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.
Key words: cilostazol • eNOS • Sirt1 • endothelial senescence
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- NO Targets SIRT1: A Novel Signaling Network in Endothelial Senescence
- Michael Potente and Stefanie Dimmeler
Arterioscler Thromb Vasc Biol 2008 28: 1577-1579.[Extract] [Full Text] [PDF]
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