Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy
Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy
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DOI：
10.1161/hh1501.094115
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发表时间：
2001-08-03
影响因子：
20.1
通讯作者：
Anversa, P
中科院分区：
文献类型：
--
作者：
Cesselli, D;Jakoniuk, I;Anversa, P
细胞死亡被认为是心力衰竭的一种机制。在这份报告中，我们验证了一种假说，即心肌细胞、内皮细胞和成纤维细胞的凋亡性死亡与心室起搏引起的扩张性肌病的发生有关。为了确定这些事件是否与起搏犬心脏细胞的死亡有关，我们检测了诸如硝基酪氨酸等活性氧产物的积累，p66(SHC)表达增强氧化应激反应，p53片段的形成，细胞色素c的释放和caspase的激活。在心功能严重受损的指标变得明显之前，检测心肌细胞、内皮细胞和成纤维细胞的凋亡。随着起搏时间的延长，细胞死亡增加，且心肌细胞死亡始终超过内皮细胞和成纤维细胞死亡。随着起搏的进行，硝基酪氨酸形成和p66(SHC)水平逐渐增加，并与细胞凋亡有关。同样，p50(Deltan)片段增加了衰竭心脏中细胞死亡的程度。此外，细胞色素c的释放和caspase-9和caspase-3的激活在起搏后1~4周增加。综上所述，在该模型中，心肌细胞死亡先于心室失代偿，并与时间依赖性的功能恶化相关。氧化应激可能是超负荷心脏细胞凋亡激活的关键。
Cell death has been questioned as a mechanism of ventricular failure. In this report, we tested the hypothesis that apoptotic death of myocytes, endothelial cells, and fibroblasts is implicated in the development of the dilated myopathy induced by ventricular pacing. Accumulation of reactive oxygen products such as nitrotyrosine, potentiation of the oxidative stress response by p66(shc) expression, formation of p53 fragments, release of cytochrome c, and caspase activation were examined to establish whether these events were coupled with apoptotic cell death in the paced dog heart. Myocyte, endothelial cell, and fibroblast apoptosis was detected before indices of severe impairment of cardiac function became apparent. Cell death increased with the duration of pacing, and myocyte death exceeded endothelial cell and fibroblast death throughout. Nitrotyrosine formation and p66(shc) levels progressively increased with pacing and were associated with cell apoptosis. Similarly, p50 (DeltaN) fragments augmented paralleling the degree of cell death in the failing heart. Moreover, cytochrome c release and activation of caspase-9 and -3 increased from 1 to 4 weeks of pacing. In conclusion, cardiac cell death precedes ventricular decompensation and correlates with the time-dependent deterioration of function in this model. Oxidative stress may be critical for activation of apoptosis in the overloaded heart.