Mitochondrial oxidative stress during cardiac lipid overload causes intracellular calcium leak and arrhythmia.
Mitochondrial oxidative stress during cardiac lipid overload causes intracellular calcium leak and arrhythmia.
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DOI：
10.1016/j.hrthm.2016.05.002
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发表时间：
2016-08
期刊：
影响因子：
5.5
通讯作者：
Morrow JP
中科院分区：
文献类型：
--
作者：
Joseph LC;Subramanyam P;Radlicz C;Trent CM;Iyer V;Colecraft HM;Morrow JP
糖尿病和肥胖与心律失常和心源性猝死的风险增加有关。在肥胖和糖尿病患者的心肌细胞中观察到异常脂质积聚，这可能有助于心律失常，但其机制尚不清楚。心脏脂质过载的转基因小鼠模型，PPARg心脏过表达小鼠，具有长QT和增加的心室异位。我们评估了这样一个假设，即心脏脂质超负荷时心室异位的增加是由于线粒体氧化应激增加导致钙处理异常所致。从成年小鼠心脏中分离心室肌细胞以记录火花和钙瞬变。小鼠被植入心律监测器用于体内记录。与对照相比，PPARg心肌细胞具有更频繁的触发活动和增加的火花。火花和触发活动减少mitotempo，一种针对性的抗氧化剂。这可以通过RyR2氧化的显著增加来解释。在PPARg心肌细胞中，钙瞬变的幅度增加，SR钙储存增加。心脏动作电位的计算机建模表明，长QT有助于增加SR钙。Mitotempo在体内减少心室异位。在心脏脂质超负荷期间，线粒体氧化应激通过氧化RyR2通道导致SR钙渗漏增加。这会促进心室异位，而心室异位在体内会被一种靶向于肾脏的抗氧化剂显著降低。这些结果表明，在肥胖和糖尿病患者中，靶向脑组织的抗氧化剂在预防心律失常和心源性猝死方面具有潜在的作用。
Diabetes and obesity are associated with an increased risk of arrhythmia and sudden cardiac death. Abnormal lipid accumulation is observed in cardiomyocytes of obese and diabetic patients, which may contribute to arrhythmia, but the mechanisms are poorly understood. A transgenic mouse model of cardiac lipid overload, the PPARg cardiac overexpression mouse, has long QT and increased ventricular ectopy. We evaluated the hypothesis that the increase in ventricular ectopy during cardiac lipid overload is caused by abnormalities in calcium handling due to increased mitochondrial oxidative stress. Ventricular myocytes were isolated from adult mouse hearts to record sparks and calcium transients. Mice were implanted with heart rhythm monitors for in vivo recordings. PPARg cardiomyocytes have more frequent triggered activity and increased sparks compared to control. Sparks and triggered activity are reduced by mitotempo, a mitochondrial-targeted antioxidant. This is explained by a significant increase in oxidation of RyR2. Calcium transients are increased in amplitude and SR calcium stores are increased in PPARg cardiomyocytes. Computer modeling of the cardiac action potential demonstrates that long QT contributes to increased SR calcium. Mitotempo decreased ventricular ectopy in vivo. During cardiac lipid overload, mitochondrial oxidative stress causes increased SR calcium leak by oxidizing RyR2 channels. This promotes ventricular ectopy, which is significantly reduced in vivo by a mitochondrial-targeted anti-oxidant. These results suggest a potential role for mitochondrial-targeted anti-oxidants to prevent arrhythmia and sudden cardiac death in obese and diabetic patients.