Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes
Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes
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DOI：
10.1093/cvr/cvv230
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发表时间：
2016-01-01
影响因子：
10.8
通讯作者：
Zhou, Lufang
中科院分区：
文献类型：
--
作者：
Goh, Kah Yong;Qu, Jing;Zhou, Lufang
在豚鼠心肌细胞中的研究表明，由少数线粒体产生的活性氧（ROS）可以传播到它们的邻居，通过ROS诱导的ROS释放（RIRR）机制触发同步的全细胞网络振荡。衰竭心脏（HF）心肌细胞中的线粒体如何对局部氧化应激扰动作出反应尚未研究。据报道，由于线粒体超微结构被破坏，在HF，和ROS信号的传播依赖于线粒体网络的完整性，我们假设，激光闪光诱导的RIRR是改变在HF。方法和结果为了检验这一假设，压力超负荷HF引起豚鼠升主动脉缩窄导致左心室扩张和射血分数下降8周后。用双光子/共聚焦显微镜研究分离的心肌细胞，以确定其基础氧化应激和响应局部激光闪光刺激而经历线粒体去极化/振荡的倾向。并对线粒体融合蛋白的表达和线粒体网络结构进行了分析。结果表明，HF心肌细胞具有较高的基线ROS水平和较少的还原型谷胱甘肽，并且更容易发生激光闪光诱导的线粒体去极化。相比之下，与假手术相比，HF心肌细胞中激光闪光和同步细胞范围内的网络振荡之间的延迟延长，并且耦合的空间范围减小，这表明抑制了RIRR和ROS信号传播。结论HF心肌线粒体间的连接被破坏，线粒体结构丧失，可能是导致ROS依赖的线粒体偶联降低的原因。
Aims Studies in guinea-pig cardiomyocytes show that reactive oxygen species (ROS) produced by a few mitochondria can propagate to their neighbours, triggering synchronized, cell-wide network oscillations via an ROS-induced ROS release (RIRR) mechanism. How mitochondria in cardiomyocytes from failing hearts (HF) respond to local oxidative stress perturbations has not been investigated. Since mitochondrial ultrastructure is reportedly disrupted in HF, and propagation of ROS signals depends on mitochondrial network integrity, we hypothesized that the laser flash-induced RIRR is altered in HF.Methods and results To test the hypothesis, pressure-overload HF was induced in guinea pigs by ascending aortic constriction leading to left ventricular dilatation and decreased ejection fraction after 8 weeks. Isolated cardiomyocytes were studied with two-photon/confocal microscopy to determine their basal oxidative stress and propensity to undergo mitochondrial depolarization/oscillations in response to local laser flash stimulations. The expression of mitofusin proteins and mitochondrial network structure were also analysed. Results showed that HF cardiomyocytes had higher baseline ROS levels and less reduced glutathione, and were more prone to laser flash-induced mitochondrial depolarization. In contrast, the delay between the laser flash and synchronized cell-wide network oscillations was prolonged in HF myocytes compared with shams, and the spatial extent of coupling was diminished, suggesting dampened RIRR and ROS signal propagation. In addition, the expressions of mitofusin proteins in HF myocardium were down-regulated compared with these from sham-operated animals, and the mitochondrial network structure altered.Conclusion The disrupted inter-mitochondrial tethering and loss of structural organization may underlie decreased ROS-dependent mitochondrial coupling in HF.