Homocysteine induces cell death in H9C2 cardiomyocytes through the generation of peroxynitrite
Homocysteine induces cell death in H9C2 cardiomyocytes through the generation of peroxynitrite
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DOI：
10.1016/j.bbrc.2007.05.147
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发表时间：
2007-08-03
影响因子：
3.1
通讯作者：
Liaudet, Lucas
中科院分区：
文献类型：
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作者：
Levrand, Sandra;Pacher, Pal;Liaudet, Lucas
同型半胱氨酸(HCY‘)对血管有毒性，但对心脏的潜在直接毒性尚不清楚。我们通过将H9C2心肌细胞暴露在HCY(0.1-5 mm)中长达6it来解决这个问题。在这些浓度下，HCY降低细胞存活率，诱导坏死和凋亡，并触发caspase-3和多聚(ADP-核糖)聚合酶(PARP)的裂解。这与细胞内产生强有力的氧化剂过氧亚硝酸盐有关。用FeTPPS分解催化剂去除过氧亚硝酸盐可显著减少乳酸脱氢酶的释放、caspase-3和PARP的DNA断裂，并恢复正常的细胞形态。在原代培养的大鼠心室肌细胞上，HCY(1 mm，6h)激活MAP激酶ERK和JNK的磷酸化，这两个重要的应激信号通路调节心肌细胞的凋亡、肥大和重构。这些结果首次证明了HCY通过产生过氧亚硝酸盐杀死心肌细胞，并激活心肌中的关键信号级联反应。(C)2007 Elsevier Inc.保留所有权利。
Homocysteine (HCY' is toxic on blood vessels, but a potential direct toxicity of HCY on the heart is unknown. We addressed this issue by exposing H9C2 cardiomyocytes to HCY (0.1-5 mM) for up to 6 It. At these concentrations, HCY reduced cell viability, induced necrosis and apoptosis and triggered the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP). This was associated with the intracellular generation of the potent oxidant peroxynitrite. Removing peroxynitrite by the decomposition catalyst FeTPPS considerably reduced LDH release, DNA fragmenta cleavage of caspase-3 and PARP, and restored normal cell morphology. In additional experiments performed in primary rat ventricular cardiomyocytes, HCY (I mM, 6 h) activated the phosphorylation of the MAP kinases ERK and JNK, two essential stress signaling kinases regulating myocardial apoptosis, hypertrophy and remodeling. These results provide the first demonstration that HCY kills cardiomyocytes through the generation of peroxynitrite and can activate key signaling cascades in the myocardium. (c) 2007 Elsevier Inc. All rights reserved.