Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo
Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo
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DOI：
10.1093/cvr/cvq373
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发表时间：
2011-02-01
影响因子：
10.8
通讯作者：
Liaudet, Lucas
中科院分区：
文献类型：
--
作者：
Loukili, Noureddine;Rosenblatt-Velin, Nathalie;Liaudet, Lucas
高迁移率族蛋白1（HMGB 1）是一种由免疫细胞主动分泌并由坏死细胞被动释放的核蛋白，其通过与晚期糖基化终产物受体结合来启动促炎信号传导。HMGB 1已被确定为心肌梗死期间的关键炎症介质，但在这种情况下负责心肌HMGB 1表达和释放的近端机制仍不清楚。在这里，我们研究了可能参与过氧亚硝酸盐，心肌梗死过程中形成的一种有效的细胞毒性氧化剂，对这些processes.Methods和结果过氧亚硝酸盐诱导坏死和HMGB 1释放的能力在体外进行了评估，在H9 C2心肌细胞和在原代小鼠心肌细胞（肌细胞和非肌细胞）。在体内，心肌HMGB 1的表达和硝基酪氨酸含量（过氧亚硝酸根生成的标志物）测定心肌缺血和再灌注大鼠，而过氧亚硝酸根的形成抑制两种不同的过氧亚硝酸根分解催化剂：5，10，15，20-四（4-磺酸基苯基）卟啉铁（III）（FeTPPS）或锰（III）-四（4-苯甲酸）卟啉氯化物（MnTBAP）。在研究的所有类型的细胞，过氧亚硝酸盐（100 μ M）引起显着的坏死，细胞内HMGB 1的损失，其被动释放到介质中。在体内，心肌缺血-再灌注诱导显著的心肌坏死、心肌硝基酪氨酸形成和心肌HMGB 1的显著过表达。FeTPPS减少硝基酪氨酸，减少梗死面积，并抑制HMGB 1过表达，与MnTBAP获得类似的效果。结论这些研究结果表明，过氧亚硝酸盐是心脏细胞HMGB 1过表达和释放的关键介质，并提供了一种新的机制，心肌氧化/亚硝化应激与梗死后心肌炎症。
Aims High-mobility group box 1 (HMGB1) is a nuclear protein actively secreted by immune cells and passively released by necrotic cells that initiates pro-inflammatory signalling through binding to the receptor for advance glycation end-products. HMGB1 has been established as a key inflammatory mediator during myocardial infarction, but the proximal mechanisms responsible for myocardial HMGB1 expression and release in this setting remain unclear. Here, we investigated the possible involvement of peroxynitrite, a potent cytotoxic oxidant formed during myocardial infarction, on these processes.Methods and results The ability of peroxynitrite to induce necrosis and HMGB1 release in vitro was evaluated in H9c2 cardiomyoblasts and in primary murine cardiac cells (myocytes and non-myocytes). In vivo, myocardial HMGB1 expression and nitrotyrosine content (a marker of peroxynitrite generation) were determined following myocardial ischaemia and reperfusion in rats, whereas peroxynitrite formation was inhibited by two different peroxynitrite decomposition catalysts: 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III) (FeTPPS) or Mn(III)-tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP). In all types of cells studied, peroxynitrite (100 mu M) elicited significant necrosis, the loss of intracellular HMGB1, and its passive release into the medium. In vivo, myocardial ischaemia-reperfusion induced significant myocardial necrosis, cardiac nitrotyrosine formation, and marked overexpression of myocardial HMGB1. FeTPPS reduced nitrotyrosine, decreased infarct size, and suppressed HMGB1 overexpression, an effect that was similarly obtained with MnTBAP.Conclusion These findings indicate that peroxynitrite represents a key mediator of HMGB1 overexpression and release by cardiac cells and provide a novel mechanism linking myocardial oxidative/nitrosative stress with post-infarction myocardial inflammation.