The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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HO-1 Induced by Cilostazol Protects Against TNF-${\alpha}$-associated Cytotoxicity via a PPAR-${\gamma}$-dependent Pathway in Human Endothelial Cells

  • Park, So-Youn (Department of Pharmacology, School of Medicine, and MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University) ;
  • Bae, Jin-Ung (Department of Pharmacology, School of Medicine, and MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University) ;
  • Hong, Ki-Whan (Department of Pharmacology, School of Medicine, and MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University) ;
  • Kim, Chi-Dae (Department of Pharmacology, School of Medicine, and MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University)
  • Received : 2011.01.23
  • Accepted : 2011.03.14
  • Published : 2011.04.30
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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 ($10{\mu}M$). 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.

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References

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