Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity
Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity
复制标题
DOI：
10.4161/auto.22971
复制
发表时间：
2013-03-01
期刊：
影响因子：
13.3
通讯作者：
Leeuwenburgh, Christiaan
中科院分区：
文献类型：
--
作者：
Dutta, Debapriya;Xu, Jinze;Leeuwenburgh, Christiaan
自噬是一种细胞自我消化过程，可介导蛋白质质量控制，并有助于预防神经退行性疾病、感染、炎症性疾病和癌症。目前的证据表明，自噬可以选择性地去除受损的细胞器，例如线粒体。线粒体诱导的氧化应激已被证明在包括心脏在内的多个器官的多种病理学中发挥重要作用。很少有研究调查增强的自噬是否可以提供针对线粒体产生的氧化应激的保护。我们使用抗霉素 A (AMA) 诱导心肌细胞中的线粒体应激，从而增加线粒体超氧化物的产生，降低线粒体膜电位并抑制细胞呼吸。此外，AMA 增强了心肌细胞中的核 DNA 氧化和细胞死亡。有趣的是，虽然氧化应激被认为可以诱导自噬，但 AMA 治疗并不会刺激心肌细胞的自噬或线粒体自噬。我们的结果表明，MTOR 抑制剂雷帕霉素诱导自噬，促进线粒体清除，并保护心肌细胞免受 AMA 的细胞毒性作用，通过小鼠心房 HL-1 心肌细胞和人心室 AC16 细胞的凋亡标记物激活和活力测定进行评估。重要的是，根据细胞呼吸、线粒体膜电位和形态分析确定，雷帕霉素改善了线粒体功能。此外，雷帕霉素诱导的自噬抑制了 AMA 诱导的泛素化蛋白的积累。通过药理学或遗传干预抑制雷帕霉素诱导的自噬减弱了雷帕霉素对 AMA 的细胞保护作用。我们提出，雷帕霉素通过去除功能失调的线粒体以及降解受损的泛素化蛋白质的组合方法，提供针对氧化应激的细胞保护作用。我们的结论是，雷帕霉素诱导的自噬可作为对抗氧化应激介导的心肌细胞损伤的潜在治疗策略。
Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. Mitochondria-induced oxidative stress has been shown to play a major role in a wide range of pathologies in several organs, including the heart. Few studies have investigated whether enhanced autophagy can offer protection against mitochondrially-generated oxidative stress. We induced mitochondrial stress in cardiomyocytes using antimycin A (AMA), which increased mitochondrial superoxide generation, decreased mitochondrial membrane potential and depressed cellular respiration. In addition, AMA augmented nuclear DNA oxidation and cell death in cardiomyocytes. Interestingly, although oxidative stress has been proposed to induce autophagy, treatment with AMA did not result in stimulation of autophagy or mitophagy in cardiomyocytes. Our results showed that the MTOR inhibitor rapamycin induced autophagy, promoted mitochondrial clearance and protected cardiomyocytes from the cytotoxic effects of AMA, as assessed by apoptotic marker activation and viability assays in both mouse atrial HL-1 cardiomyocytes and human ventricular AC16 cells. Importantly, rapamycin improved mitochondrial function, as determined by cellular respiration, mitochondrial membrane potential and morphology analysis. Furthermore, autophagy induction by rapamycin suppressed the accumulation of ubiquitinylated proteins induced by AMA. Inhibition of rapamycin-induced autophagy by pharmacological or genetic interventions attenuated the cytoprotective effects of rapamycin against AMA. We propose that rapamycin offers cytoprotection against oxidative stress by a combined approach of removing dysfunctional mitochondria as well as by degrading damaged, ubiquitinated proteins. We conclude that autophagy induction by rapamycin could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes.