Heart failure, mostly associated with cardiac hypertrophy, is still a major cause of illness and death. Oxidative stress causes contractile failure and the accumulation of reactive oxygen species leads to mitochondrial dysfunction, associated with aging and heart failure, suggesting that mitochondria-targeted therapies could be effective in this context. The purpose of this work was to characterize how mitochondrial oxidative stress is involved in cardiac hypertrophy development and to determine if mitochondria-targeted therapies could improve cardiac phenotypes. We used neonatal and adult rat cardiomyocytes (NCMs and ACMs) hypertrophied by isoproterenol (Iso) to induce an increase of mitochondrial superoxide anion. Superoxide dismutase 2 activity and mitochondrial biogenesis were significantly decreased after 24h of Iso treatment. To counteract the mitochondrial oxidative stress induced by hypertrophy, we evaluated the impact of two different anti-oxidants, mitoquinone (MitoQ) and EUK 134. Both significantly decreased mitochondrial superoxide anion and hypertrophy in hypertrophied NCMs and ACMs. Conversely to EUK 134 which preserved cell functions, MitoQ impaired mitochondrial function by decreasing maximal mitochondrial respiration, mitochondrial membrane potential and mitophagy (particularly Parkin expression) and altering mitochondrial structure. The same decrease of Parkin was found in human cardiomyocytes but not in fibroblasts suggesting a cell specificity deleterious effect of MitoQ. Our data showed the importance of mitochondrial oxidative stress in the development of cardiomyocyte hypertrophy. Interestingly, we observed that targeting mitochondria by an anti-oxidant (MitoQ) impaired metabolism specifically in cardiomyocytes. Conversely, the SOD mimic (EUK 134) decreased both oxidative stress and cardiomyocyte hypertrophy and restored impaired cardiomyocyte metabolism and mitochondrial biogenesis.

中文翻译：

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还原线粒体对于预防肥大过程中的心脏氧化应激至关重要

主要与心脏肥大有关的心力衰竭仍然是疾病和死亡的主要原因。氧化应激会导致收缩衰竭，而活性氧的积累会导致线粒体功能障碍，与衰老和心力衰竭相关，这表明针对这种情况的针对线粒体的疗法可能有效。这项工作的目的是表征线粒体氧化应激如何参与心脏肥大的发展，并确定针对线粒体的疗法是否可以改善心脏表型。我们使用了由异丙肾上腺素（Iso）肥大的新生和成年大鼠心肌细胞（NCM和ACM）来诱导线粒体超氧阴离子的增加。Iso处理24小时后，超氧化物歧化酶2活性和线粒体生物发生显着降低。为了抵消肥大引起的线粒体氧化应激，我们评估了两种不同的抗氧化剂米托醌（MitoQ）和EUK 134的影响。肥大的NCM和ACM中线粒体超氧阴离子和肥大均显着降低。与保留细胞功能的EUK 134相反，MitoQ通过降低最大线粒体呼吸，线粒体膜电位和线粒体（特别是帕金因表达）并改变线粒体结构来损害线粒体功能。在人心肌细胞中发现了帕金相同的减少，但在成纤维细胞中却没有，这表明MitoQ具有细胞特异性的有害作用。我们的数据表明线粒体氧化应激在心肌细胞肥大发展中的重要性。有趣的是 我们观察到，通过抗氧化剂（MitoQ）靶向线粒体会特别损害心肌细胞的新陈代谢。相反，SOD模拟物（EUK 134）减少了氧化应激和心肌细胞肥大，并恢复了受损的心肌细胞代谢和线粒体生物发生。