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首页> 外文期刊>The Korean Journal of Physiology & Pharmacology >HO-1 Induced by Cilostazol Protects Against TNF-α-associated Cytotoxicity via a PPAR-γ-dependent Pathway in Human Endothelial Cells
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HO-1 Induced by Cilostazol Protects Against TNF-α-associated Cytotoxicity via a PPAR-γ-dependent Pathway in Human Endothelial Cells

机译：西洛他唑诱导的HO-1通过PPAR-γ依赖性途径保护人内皮细胞抗TNF-α相关的细胞毒性。

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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-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.
机译：大量证据表明，内源性抗氧化蛋白的诱导似乎是延迟细胞损伤进程的合理策略。在我们先前的研究中，发现西洛他唑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，进行本研究以检查西洛他唑是否能够通过诱导HO-1表达来抵消内皮细胞中肿瘤坏死因子-α（TNF-α）-诱导的细胞死亡。我们将人脐静脉内皮细胞（HUVEC）暴露于TNF-α（50 ng / ml），有或没有西洛他唑（10μM）。用西洛他唑预处理可显着降低HUVEC中TNF-α诱导的活力丧失，这一点可通过HO-1抑制剂锌原卟啉IX（ZnPP）逆转。此外，西洛他唑增加了HO-1蛋白和mRNA表达。西洛他唑诱导的HO-1诱导不仅被ZnPP减弱，而且被铜原卟啉IX（CuPP）减弱。在测定过氧化物酶体增殖物激活的受体-γ（PPAR-γ）转录活性的测定中，西洛他唑直接增加了PPAR-γ的转录活性，这被HO-1抑制剂完全废除了。此外，在用HO-1 siRNA转染的细胞中，西洛他唑和罗格列酮增加的PPAR-γ活性被完全消除。两者合计，这些结果表明西洛他唑通过PPAR-γ依赖性途径上调HO-1并保护细胞免受TNF-α诱导的内皮细胞毒性。

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