Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck)
Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck)
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抗氧化防御和心律失常的保护：来自哺乳动物冬眠者（土拨鼠）的教训
DOI：
10.1096/fj.201701516r
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Lai-Hua Xie
中科院分区：
文献类型：
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作者：
Zhenghang Zhao;Raymond K. Kudej;Hairuo Wen;Nadezhda Fefelova;Lin Yan;Dorothy E. Vatner;Stephen F. Vatner;Lai-Hua Xie
冬眠动物对低温引起的心律失常表现出抵抗力。然而，目前尚不清楚哺乳动物冬眠者是否以及如何抵抗缺血引起的心律失常。本研究的目的是确定土拨鼠（Marmota monax）在冬季、冬眠期和夏季（不冬眠期）的相同室温下冠状动脉闭塞后对心律失常的易感性及其机制。通过监测遥测心电图，我们发现夏季土拨鼠的心律失常评分（以心律失常严重程度计算）、室性心动过速、心室颤动以及心源性猝死（SCD）的发生率明显高于冬季。冬季土拨鼠心脏中过氧化氢酶的表达水平明显高于夏季，而氧化Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）的水平低于夏季。与夏季土拨鼠分离的心室肌细胞相比，冬季土拨鼠分离的心室肌细胞对 H2O2 诱导的早期后除极 (EAD) 具有更强的抵抗力。通过抑制 CaMKII（使用 KN-93）、l 型 Ca 电流（使用硝苯地平）或晚 Na+ 电流（使用雷诺嗪）来消除 EAD。在土拨鼠中，夏季，通过过氧化氢酶（通过腺病毒载体）过度表达或抑制心脏中的 CaMKII（使用 KN-93），心律失常评分显着降低。这项研究表明，冬眠哺乳动物的心脏在冬季对缺血引起的心律失常和 SCD 具有更强的抵抗力。抗氧化能力的增强和 CaMKII 活性的降低可能使土拨鼠心脏在冬季能够抵抗 EAD 和心律失常。在这种新型自然动物模型中过氧化氢酶过表达或 CaMKII 抑制所赋予的深刻保护可能为心律失常治疗的临床方向提供见解。-Zhao, Z.、Kudej, R.K.、Wen, H.、Fefelova, N.、Yan, L.、Vatner, D. E.、Vatner, S. F.、Xie, L.-H.抗氧化防御和心律失常的保护：来自哺乳动物冬眠者（土拨鼠）的教训。
Hibernating animals show resistance to hypothermia-induced cardiac arrhythmias. However, it is not clear whether and how mammalian hibernators are resistant to ischemia-induced arrhythmias. The goal of this investigation was to determine the susceptibility of woodchucks (Marmota monax) to arrhythmias and their mechanisms after coronary artery occlusion at the same room temperature in both winter, the time for hibernation, and summer, when they do not hibernate. By monitoring telemetric electrocardiograms, we found significantly higher arrhythmia scores, calculated as the severity of arrhythmias, with incidence of ventricular tachycardia, ventricular fibrillation, and thus sudden cardiac death (SCD) in woodchucks in summer than they had in winter. The level of catalase expression in woodchuck hearts was significantly higher, whereas the level of oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) was lower in winter than it was in summer. Ventricular myocytes isolated from woodchucks in winter were more resistant to H2O2-induced early afterdepolarizations (EADs) compared with myocytes isolated from woodchucks in summer. The EADs were eliminated by inhibiting CaMKII (with KN-93), l-type Ca current (with nifedipine), or late Na+ current (with ranolazine). In woodchucks, in the summer, the arrhythmia score was significantly reduced by overexpression of catalase (via adenoviral vectors) or the inhibition of CaMKII (with KN-93) in the heart. This study suggests that the heart of the mammalian hibernator is more resistant to ischemia-induced arrhythmias and SCD in winter. Increased antioxidative capacity and reduced CaMKII activity may confer resistance in woodchuck hearts against EADs and arrhythmias during winter. The profound protection conferred by catalase overexpression or CaMKII inhibition in this novel natural animal model may provide insights into clinical directions for therapy of arrhythmias.—Zhao, Z., Kudej, R. K., Wen, H., Fefelova, N., Yan, L., Vatner, D. E., Vatner, S. F., Xie, L.-H. Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck).