HO-1 Induced by Cilostazol Protects Against TNF-alpha-associated Cytotoxicity via a PPAR-gamma-dependent Pathway in Human Endothelial Cells.
10.4196/kjpp.2011.15.2.83
- Author:
So Youn PARK
1
;
Jin Ung BAE
;
Ki Whan HONG
;
Chi Dae KIM
Author Information
1. Department of Pharmacology, School of Medicine, and MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Yangsan 626-770, Korea. chidkim@pusan.ac.kr
- Publication Type:Original Article
- Keywords:
Cilosatzol;
PPAR-gamma;
HO-1;
Endothelial cells
- MeSH:
Cell Death;
Endothelial Cells;
Heme Oxygenase-1;
Human Umbilical Vein Endothelial Cells;
Humans;
Peroxisomes;
Proteins;
RNA, Messenger;
RNA, Small Interfering;
Tetrazoles;
Thiazolidinediones;
Tumor Necrosis Factor-alpha;
Zinc
- From:The Korean Journal of Physiology and Pharmacology
2011;15(2):83-88
- CountryRepublic of Korea
- Language:English
-
Abstract:
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-alpha (TNF-alpha)-induced cell death in endothelial cells via the induction of HO-1 expression. We exposed human umbilical vein endothelial cells (HUVECs) to TNF-alpha (50 ng/ml), with or without cilostazol (10 microM). Pretreatment with cilostazol markedly reduced TNF-alpha-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-gamma (PPAR-gamma) transcription activity, cilostazol directly increased PPAR-gamma transcriptional activity which was completely abolished by HO-1 inhibitor. Furthermore, increased PPAR-gamma 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-alpha-induced endothelial cytotoxicity via a PPAR-gamma-dependent pathway.
