Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo
Peroxynitrite is a major trigger of cardiomyocyte apoptosis in vitro and in vivo
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DOI：
10.1016/j.freeradbiomed.2006.04.034
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发表时间：
2006-09-15
影响因子：
7.4
通讯作者：
Liaudet, Lucas
中科院分区：
文献类型：
--
作者：
Levrand, Sandra;Vannay-Bouchiche, Christine;Liaudet, Lucas
最近的证据表明，过氧亚硝酸盐是心脏疾病中的主要细胞毒性效应物，但其作用机制仍不确切。值得注意的是，过氧亚硝酸盐触发心肌细胞凋亡的能力，在许多心脏疾病中细胞死亡的一种重要模式，仍然很难定义。我们评估了培养的H9 C2心肌细胞的凋亡和坏死细胞死亡，短暂（20分钟）暴露于过氧亚硝酸盐（50-500 μ M）。过氧亚硝酸盐依赖的心肌毒性，然后在心肌缺血-再灌注（MIR）的大鼠模型中进行了研究，其中过氧亚硝酸盐的影响被超氧化物歧化酶模拟物和过氧亚硝酸盐清除剂锰（III）-四（4-苯甲酸）卟啉（MnTBAP）阻断。在体外，过氧亚硝酸盐主要通过凋亡（DNA片段化，凋亡性核改变，caspase-3激活和PARP裂解）杀死心肌细胞，但不通过坏死（碘化丙啶染色和LDH释放）。在体内，MIR触发心肌氧化应激（丙二醛生成）、硝基酪氨酸形成、中性粒细胞蓄积以及caspase-3和PARP裂解，表明正在进行的心肌细胞凋亡。MnTBAP抑制这些变化，使心肌损伤大大减少。因此，过氧亚硝酸盐引发心肌细胞凋亡在体外和心肌在体内，通过一个途径，涉及半胱天冬酶-3激活和PARR的裂解。这些结果提供了重要的新的信息过氧亚硝酸盐的心肌毒性的机制。(c)2006年由Elsevier Inc.出版
Recent evidence indicates that peroxynitrite represents a major cytotoxic effector in heart diseases, but its mechanisms of action are still not known exactly. Notably, the ability of peroxynitrite to trigger cardiomyocyte apoptosis, a crucial mode of cell death in many cardiac conditions, remains poorly defined. We evaluated apoptotic and necrotic cell death in cultured H9C2 cardiomyocytes, following a brief (20 min) exposure to peroxynitrite (50-500 mu M). Peroxynitrite-dependent myocardial toxicity was then investigated in a rat model of myocardial ischemia-reperfusion (MIR), where the effects of peroxynitrite were blocked by the superoxide dismutase mimetics and peroxynitrite scavenger Mn(III)-tetrakis(4-benzoic acid) porphyrin (MnTBAP). In vitro, peroxynitrite killed cardiomyocytes mostly through apoptosis (DNA fragmentation, apoptotic nuclear alterations, caspase-3 activation, and PARP cleavage), but not necrosis (propidium iodide staining and LDH release). In vivo, MIR triggered myocardial oxidative stress (malondialdehyde generation), nitrotyrosine formation, neutrophil accumulation, and the cleavage of caspase-3 and PARP, indicating ongoing myocardial apoptosis. MnTBAP suppressed these alterations, allowing a considerable reduction of myocardial injury. Thus, peroxynitrite triggers apoptosis in cardiomyocytes in vitro and in the myocardium in vivo, through a pathway involving caspase-3 activation and the cleavage of PARR These results provide important novel information on the mechanisms of myocardial toxicity of peroxynitrite. (c) 2006 Published by Elsevier Inc.