Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy.
Department of Medicine, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK.
Free Radic Biol Med. 2019 Apr;134:678-687. doi: 10.1016/j.freeradbiomed.2019.01.034. Epub 2019 Feb 4.
Reactive oxygen species (ROS) have an equivocal role in myocardial ischaemia reperfusion injury. Within the cardiomyocyte, mitochondria are both a major source and target of ROS. We evaluate the effects of a selective, dose-dependent increase in mitochondrial ROS levels on cardiac physiology using the mitochondria-targeted redox cycler MitoParaquat (MitoPQ). Low levels of ROS decrease the susceptibility of neonatal rat ventricular myocytes (NRVMs) to anoxia/reoxygenation injury and also cause profound protection in an in vivo mouse model of ischaemia/reperfusion. However higher doses of MitoPQ resulted in a progressive alteration of intracellular [Ca] homeostasis and mitochondrial function in vitro, leading to dysfunction and death at high doses. Our data show that a primary increase in mitochondrial ROS can alter cellular function, and support a hormetic model in which low levels of ROS are cardioprotective while higher levels of ROS are cardiotoxic.
活性氧 (ROS) 在心肌缺血再灌注损伤中具有双重作用。在线粒体中，ROS 既是主要来源也是靶点。我们使用线粒体靶向氧化还原环 MitoParaquat（MitoPQ）评估了线粒体 ROS 水平选择性、剂量依赖性增加对心脏生理学的影响。低水平的 ROS 可降低新生大鼠心室肌细胞（NRVM）对缺氧/复氧损伤的敏感性，并且在缺血/再灌注的体内小鼠模型中也能引起显著的保护作用。然而，更高剂量的 MitoPQ 导致体外细胞内 [Ca] 稳态和线粒体功能的逐渐改变，导致在高剂量下功能障碍和死亡。我们的数据表明，线粒体 ROS 的主要增加可以改变细胞功能，并支持一种低水平 ROS 具有心脏保护作用而高水平 ROS 具有心脏毒性的激效模型。
