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KMID : 0811720110150020083
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Korean Journal of Physiology & Pharmacology
2011 Volume.15 No. 2 p.83 ~ p.88
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HO-1 Induced by Cilostazol Protects Against TNF-?-associated Cytotoxicity via a PPAR-?-dependent Pathway in Human Endothelial Cells
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Park So-Youn
Bae Jin-Ung
Hong Ki-Whan
Kim Chi-Dae
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Abstract
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A large body of evidence has indicated that induction of endogenous antioxidative proteins seems to be a reasonable strategy for delaying the progression of cell injury. In our previous study, cilostazol was found to increase the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in synovial cells. Thus, the present study was undertaken to examine whether cilostazol is able to counteract tumor necrosis factor-? (TNF-?)-induced cell death in endothelial cells via the induction of HO-1 expression. We exposed human umbilical vein endothelial cells (HUVECs) to TNF-? (50 ng/ml), with or without cilostazol (10?M). Pretreatment with cilostazol markedly reduced TNF-?-induced viability loss in the HUVECs, which was reversed by zinc protoporphyrine IX (ZnPP), an inhibitor of HO-1. Moreover, cilostazol increased HO-1 protein and mRNA expression. Cilostazol-induced HO-1 induction was markedly attenuated not only by ZnPP but also by copper-protoporphyrin IX (CuPP). In an assay measuring peroxisome proliferator-activated receptor-? (PPAR-?) transcription activity, cilostazol directly increased PPAR-? transcriptional activity which was completely abolished by HO-1 inhibitor. Furthermore, increased PPAR-? activity by cilostazol and rosiglitazone was completely abolished in cells transfected with HO-1 siRNA. Taken together, these results indicate that cilostazol up-regulates HO-1 and protects cells against TNF-?-induced endothelial cytotoxicity via a PPAR-?- dependent pathway.
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KEYWORD
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Cilosatzol, PPAR-?, HO-1, Endothelial cells
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