Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice.
Mitochondrial Oxidative Stress Mediates Bradyarrhythmia in Leigh Syndrome Mitochondrial Disease Mice.
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线粒体氧化应激介导Leigh综合征线粒体病小鼠的缓慢性心律失常。
DOI：
10.3390/antiox12051001
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发表时间：
2023-04-26
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影响因子：
--
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中科院分区：
文献类型：
--
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线粒体氧化应激与衰老和几种心血管疾病有关，包括心力衰竭和心肌病、室性心动过速和心房纤颤。线粒体氧化应激在缓慢性心律失常中的作用尚不清楚。具有Ndufs 4亚基呼吸复合物I的种系缺失的小鼠发展类似Leigh综合征（LS）的严重线粒体脑肌病。LS小鼠中存在几种类型的心脏缓慢性心律失常，包括频繁的窦房结功能障碍和阵发性房室（AV）阻滞。用线粒体抗氧化剂Mitotempo或线粒体保护肽SS31治疗显著改善了缓慢性心律失常并延长了LS小鼠的寿命。使用离体Langendorff灌注心脏与线粒体和总细胞活性氧（ROS）的共聚焦成像，我们发现增加的ROS在LS心脏，这是由缺血再灌注增强。同步ECG记录显示窦房结功能障碍和AV阻滞，同时伴有氧化应激的严重程度。Mitotempo治疗消除ROS并恢复窦性心律。我们的研究揭示了在LS线粒体心肌病的背景下，线粒体和总ROS在缓慢性心律失常中的直接机制作用的有力证据。我们的研究还支持了靶向抗氧化剂或SS31治疗LS患者的潜在临床应用。
Mitochondrial oxidative stress has been implicated in aging and several cardiovascular diseases, including heart failure and cardiomyopathy, ventricular tachycardia, and atrial fibrillation. The role of mitochondrial oxidative stress in bradyarrhythmia is less clear. Mice with a germline deletion of Ndufs4 subunit respiratory complex I develop severe mitochondrial encephalomyopathy resembling Leigh Syndrome (LS). Several types of cardiac bradyarrhythmia are present in LS mice, including a frequent sinus node dysfunction and episodic atrioventricular (AV) block. Treatment with the mitochondrial antioxidant Mitotempo or mitochondrial protective peptide SS31 significantly ameliorated the bradyarrhythmia and extended the lifespan of LS mice. Using an ex vivo Langendorff perfused heart with live confocal imaging of mitochondrial and total cellular reactive oxygen species (ROS), we showed increased ROS in the LS heart, which was potentiated by ischemia-reperfusion. A simultaneous ECG recording showed a sinus node dysfunction and AV block concurrent with the severity of the oxidative stress. Treatment with Mitotempo abolished ROS and restored the sinus rhythm. Our study reveals robust evidence of the direct mechanistic roles of mitochondrial and total ROS in bradyarrhythmia in the setting of LS mitochondrial cardiomyopathy. Our study also supports the potential clinical application of mitochondrial-targeted antioxidants or SS31 for the treatment of LS patients.
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影响因子：
10.8
作者：
Dai, Dao-Fu;Hsieh, Edward J.;Rabinovitch, Peter S.
通讯作者：
Rabinovitch, Peter S.
影响因子：
9.7
作者：
Dai, Dao-Fu;Hsieh, Edward J.;Rabinovitch, Peter S.
通讯作者：
Rabinovitch, Peter S.
DOI：
10.1073/pnas.1006214107
发表时间：
2010-06-15
影响因子：
11.1
作者：
Quintana, Albert;Kruse, Shane E.;Palmiter, Richard D.
通讯作者：
Palmiter, Richard D.
影响因子：
4.8
作者：
Mitchell, Wayne;Ng, Emily A.;Alder, Nathan N.
通讯作者：
Alder, Nathan N.
影响因子：
15.9
作者：
Cai, Shanshan;Zhao, Mingyue;Zhou, Bo;Yoshii, Akira;Bugg, Darrian;Villet, Outi;Sahu, Anita;Olson, Gregory S;Davis, Jennifer;Tian, Rong
通讯作者：
Tian, Rong