From the Department of Physiology and Biophysics, Rush University, Chicago, IL (J.Y., W.Z., D.M.D., E.C., M.F., X.A.); Department of Cell and Molecular Physiology (J.Y., W.Z., J.K.T., X.G., D.M.D., E.C., X.W., X.A.) and Department of Thoracic and Cardiovascular Surgery (M.B.), Loyola University Chicago, Maywood, IL; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (B.C., L.-S.S.); Department of Pharmacology, University of California at Davis (K.S.G., D.M.B.); and Department of Internal Medicine, Johns Hopkins University, Baltimore, MD (M.E.A.).
Circ Res. 2018 Mar 16;122(6):821-835. doi: 10.1161/CIRCRESAHA.117.312536. Epub 2018 Jan 19.
Atrial fibrillation (AF) is the most common arrhythmia, and advanced age is an inevitable and predominant AF risk factor. However, the mechanisms that couple aging and AF propensity remain unclear, making targeted therapeutic interventions unattainable.
To explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca handling and consequently Ca-mediated atrial arrhythmias.
We used a series of cutting-edge electrophysiological and molecular techniques, exploited the power of transgenic mouse models to detail the molecular mechanism, and verified its clinical applicability in parallel studies on donor human hearts. We discovered that significantly increased activity of the stress response kinase JNK2 (JNK isoform 2) in the aged atria is involved in arrhythmic remodeling. The JNK-driven atrial proarrhythmic mechanism is supported by a pathway linking JNK, CaMKII (Ca/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca leak mediated by RyR2 channels. This leads to aberrant intracellular Ca waves and enhanced AF propensity. In contrast, this mechanism is absent in young atria. In JNK challenged animal models, this is eliminated by JNK2 ablation or CaMKII inhibition.
We have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.
心房颤动（AF）是最常见的心律失常，高龄是不可避免的、主要的房颤危险因素。然而，将衰老和房颤易感性联系起来的机制尚不清楚，使得靶向治疗干预无法实现。
探讨重要应激反应 JNK（c-Jun N-末端激酶）在肌浆网 Ca 处理中的功能作用，以及随后 Ca 介导的心房心律失常。
我们使用了一系列先进的电生理和分子技术，利用转基因小鼠模型的优势详细研究了分子机制，并在对供体人心的平行研究中验证了其临床适用性。我们发现，衰老心房中应激反应激酶 JNK2（JNK 同工型 2）的活性显著增加，与心律失常重构有关。JNK 驱动的心房致心律失常机制得到了一条途径的支持，该途径将 JNK、CaMKII（Ca/钙调蛋白依赖性激酶 II）和肌浆网 Ca 释放 RyR2（兰尼碱受体）通道联系起来。JNK2 激活 CaMKII，这是心肌中一种关键的致心律失常分子。反过来，激活的 CaMKII 上调了由 RyR2 通道介导的舒张期肌浆网 Ca 泄漏。这导致异常的细胞内 Ca 波，并增强了房颤的易感性。相比之下，这种机制在年轻的心房中不存在。在 JNK 挑战的动物模型中，这种机制被 JNK2 消融或 CaMKII 抑制所消除。
我们已经确定 JNK2 驱动的 CaMKII 激活是激酶串扰的一种新方式，也是心房心律失常重构的因果因素，这使得 JNK2 成为预防和治疗房颤的一个有吸引力的新治疗靶点。
