TY - JOUR
T1 - Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells
AU - Ota, Hidetaka
AU - Eto, Masato
AU - Kano, Mitsunobu R.
AU - Ogawa, Sumito
AU - Iijima, Katsuya
AU - Akishita, Masahiro
AU - Ouchi, Yasuyoshi
PY - 2008/9/1
Y1 - 2008/9/1
N2 - 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.
AB - 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.
KW - Cilostazol
KW - Endothelial senescence
KW - Sirt1
KW - eNOS
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U2 - 10.1161/ATVBAHA.108.164368
DO - 10.1161/ATVBAHA.108.164368
M3 - Article
C2 - 18556572
AN - SCOPUS:51649106480
SN - 1079-5642
VL - 28
SP - 1634
EP - 1639
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 9
ER -