Peroxynitrite is a potent inhibitor of NF-κB activation triggered by inflammatory stimuli in cardiac and endothelial cell lines
Peroxynitrite is a potent inhibitor of NF-κB activation triggered by inflammatory stimuli in cardiac and endothelial cell lines
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DOI：
10.1074/jbc.m501977200
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发表时间：
2005-10-14
影响因子：
4.8
通讯作者：
Liaudet, L
中科院分区：
文献类型：
--
作者：
Levrand, S;Pesse, B;Liaudet, L
过氧亚硝酸盐是一种有效的氧化剂和硝化物质，被认为是许多心脏病理中心肌损伤的直接效应物。过氧亚硝酸盐是否也通过调节心肌细胞信号转导间接起作用，尚未研究。因此，我们研究了过氧亚硝酸盐在培养的H9 C2心肌细胞中激活NF-κ B（一种重要的促炎转录因子）的可能作用。H9 C2细胞用肿瘤坏死因子-α或脂多糖刺激后，短暂（20分钟）暴露于过氧亚硝酸盐。脂多糖或肿瘤坏死因子-α引发的NF-κ B活化（其抑制剂I κ B α的磷酸化和降解、NF-κ B p65的核转位和NF-κ B DNA结合）被过氧亚硝酸盐消除。过氧亚硝酸盐还抑制了两种人内皮细胞系中的NF-κ B B，这些细胞系被肿瘤坏死因子-α或白细胞介素-1 β激活。这些影响与氧化化学有关，但与硝化化学无关，并且在硝化被表儿茶素抑制的同时仍在观察。过氧亚硝酸盐抑制NF-κ B的机制是完全阻断上游激酶I κ B激酶（IKK）β的磷酸化和激活，这是典型的促炎性NF-κ B激活所必需的。同时，过氧亚硝酸盐激活NF-κ B诱导激酶和IKK α的磷酸化，被认为是替代的非经典NF-κ B激活途径的一部分。IKK β依赖性NF-κ B B激活的抑制转化为过氧亚硝酸盐对NF-κ B依赖性基因转录的显著抑制。因此，过氧亚硝酸盐对NF-κ B具有双重作用，抑制经典IKK β依赖性NF-κ B活化，同时激活NF-κ B诱导激酶和IKK α磷酸化，这表明其参与NF-κ B活化的替代途径。这些发现为理解氧化还原应激与炎症之间的关系提供了新的视角。
Peroxynitrite is a potent oxidant and nitrating species proposed as a direct effector of myocardial damage in numerous cardiac pathologies. Whether peroxynitrite also acts indirectly, by modulating cell signal transduction in the myocardium, has not been investigated. Therefore, we examined a possible role for peroxynitrite on the activation of NF-kappa B, a crucial pro-inflammatory transcription factor, in cultured H9C2 cardiomyocytes. H9C2 cells were stimulated with tumor necrosis factor-alpha or lipopolysaccharide following a brief (20-min) exposure to peroxynitrite. NF-kappa B activation ( phosphorylation and degradation of its inhibitor I kappa B alpha, nuclear translocation of NF-kappa B p65, and NF-kappa B DNA binding) triggered by lipopolysaccharide or tumor necrosis factor-alpha was abrogated by peroxynitrite. Peroxynitrite also inhibited NF-kappa B in two human endothelial cell lines activated with tumor necrosis factor-alpha or interleukin-1 beta. These effects were related to oxidative but not nitrative chemistry and were still being observed while nitration was suppressed by epicatechin. The mechanism of NF-kappa B inhibition by peroxynitrite was a complete blockade of phosphorylation and activation of the upstream kinase I kappa B kinase (IKK) beta, required for canonical, pro-inflammatory NF-kappa B activation. At the same time, peroxynitrite activated phosphorylation of NF-kappa B-inducing kinase and IKK alpha, considered as part of an alternative, noncanonical NF-kappa B activation pathway. Suppression of IKK beta-dependent NF-kappa B activation translated into a marked inhibition of the transcription of NF-kappa B-dependent genes by peroxynitrite. Thus, peroxynitrite has a dual effect on NF-kappa B, inhibiting canonical IKK beta-dependent NF-kappa B activation while activating NF-kappa B-inducing kinase and IKK alpha phosphorylation, which suggests its involvement in an alternative pathway of NF-kappa B activation. These findings offer new perspectives for the understanding of the relationships between redox stress and inflammation.