Department of Pharmacology, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, New Jersey, USA.
FASEB J. 2018 Aug;32(8):4229-4240. doi: 10.1096/fj.201701516R. Epub 2018 Feb 28.
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 Ca/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 HO-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).
冬眠动物对低温诱导的心律失常具有抵抗力。然而，目前尚不清楚哺乳动物冬眠动物是否以及如何对缺血性心律失常具有抵抗力。本研究的目的是确定土拨鼠（ Marmota monax）在冬季（冬眠时间）和夏季（不冬眠）同一室温下冠状动脉闭塞后的心律失常易感性及其机制。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明显更高，计算为心律失常的严重程度，室性心动过速、心室颤动的发生率以及因此导致的心脏性猝死（SCD）发生率均高于冬季。冬季土拨鼠心脏中的过氧化氢酶表达水平明显升高，而氧化钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）的水平则低于夏季。与夏季分离的土拨鼠心室肌细胞相比，冬季分离的土拨鼠心室肌细胞对 HO 诱导的早期后除极（EAD）更具抵抗力。EAD 被抑制 CaMKII（用 KN-93）、L 型钙电流（用硝苯地平）或晚期 Na 电流（用雷诺嗪）消除。在夏季，通过过表达过氧化氢酶（通过腺病毒载体）或抑制 CaMKII（用 KN-93），土拨鼠的心律失常评分显著降低。这项研究表明，哺乳动物冬眠动物的心脏在冬季对缺血性心律失常和 SCD 的抵抗力更强。抗氧化能力的增加和 CaMKII 活性的降低可能使土拨鼠心脏在冬季抵抗 EAD 和心律失常。这种新型天然动物模型中过氧化氢酶过表达或 CaMKII 抑制所提供的深刻保护可能为心律失常治疗的临床方向提供新的见解。-赵、Kudej、R.K.、Wen、H.、Fefelova、N.、Yan、L.、Vatner、D.E.、Vatner、S.F.、Xie、L.-H. 抗氧化防御和保护对抗心律失常：来自哺乳动物冬眠者（土拨鼠）的教训。
