Department of Pharmacology, School of Medicine, and MRC for Ischemic Tissue Regeneration and Medical Research Institute, Pusan National University, Yangsan 626-770, Korea.
Korean J Physiol Pharmacol. 2011 Apr;15(2):83-8. doi: 10.4196/kjpp.2011.15.2.83. Epub 2011 Apr 30.
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-α (TNF-α)-induced cell death in endothelial cells via the induction of HO-1 expression. We exposed human umbilical vein endothelial cells (HUVECs) to TNF-α (50 ng/ml), with or without cilostazol (10 µM). Pretreatment with cilostazol markedly reduced TNF-α-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-γ (PPAR-γ) transcription activity, cilostazol directly increased PPAR-γ transcriptional activity which was completely abolished by HO-1 inhibitor. Furthermore, increased PPAR-γ 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-α-induced endothelial cytotoxicity via a PPAR-γ-dependent pathway.
大量证据表明，诱导内源性抗氧化蛋白似乎是延缓细胞损伤进展的合理策略。在我们之前的研究中，西洛他唑被发现能增加滑膜细胞中抗氧化酶血红素加氧酶-1（HO-1）的表达。因此，本研究旨在探讨西洛他唑是否能通过诱导 HO-1 表达来抵抗肿瘤坏死因子-α（TNF-α）诱导的内皮细胞死亡。我们将人脐静脉内皮细胞（HUVEC）暴露于 TNF-α（50ng/ml）中，同时或不同时用西洛他唑（10μM）预处理。西洛他唑预处理明显减少了 TNF-α诱导的 HUVEC 活力丧失，而 HO-1 抑制剂锌原卟啉 IX（ZnPP）则逆转了这一作用。此外，西洛他唑增加了 HO-1 蛋白和 mRNA 的表达。不仅 ZnPP，铜原卟啉 IX（CuPP）也明显减弱了西洛他唑诱导的 HO-1 诱导。在过氧化物酶体增殖物激活受体-γ（PPAR-γ）转录活性测定中，西洛他唑直接增加了 PPAR-γ 的转录活性，而 HO-1 抑制剂则完全消除了这种活性。此外，用 HO-1 siRNA 转染的细胞中，西洛他唑和罗格列酮增加的 PPAR-γ 活性也完全被消除。综上所述，这些结果表明，西洛他唑通过 PPAR-γ 依赖性途径上调 HO-1，保护细胞免受 TNF-α 诱导的内皮细胞毒性。
