Cardiovascular Research Institute, Dept of Molecular Physiology & Biophysics and Medicine (Cardiology), Baylor College of Medicine, Houston, TX.
Institute of Pharmacology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
J Am Coll Cardiol. 2013 Nov 19;62(21):2010-9. doi: 10.1016/j.jacc.2013.06.052. Epub 2013 Aug 21.
This study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF).
JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca(2+) handling and modulation of ryanodine receptor Ca(2+) channels (RyR2). Whereas defective RyR2-mediated Ca(2+) release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias.
Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF). Pseudoknock-in (PKI) mouse models were generated to determine the molecular defects underlying the development of AF caused by this JPH2 mutation.
PKI mice expressing E169K mutant JPH2 exhibited a higher incidence of inducible AF than wild type (WT)-PKI mice, whereas A399S-PKI mice expressing a hypertrophic cardiomyopathy-linked JPH2 mutation not associated with atrial arrhythmias were not significantly different from WT-PKI. E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca(2+) release events. These changes were attributed to reduced binding of E169K-JPH2 to RyR2. Atrial JPH2 levels in WT-JPH2 transgenic, nontransgenic, and JPH2 knockdown mice correlated negatively with the incidence of pacing-induced AF. Ca(2+) spark frequency in atrial myocytes and the open probability of single RyR2 channels from JPH2 knockdown mice was significantly reduced by a small JPH2-mimicking oligopeptide. Moreover, patients with pAF had reduced atrial JPH2 levels per RyR2 channel compared to sinus rhythm patients and an increased frequency of spontaneous Ca(2+) release events.
Our data suggest a novel mechanism by which reduced JPH2-mediated stabilization of RyR2 due to loss-of-function mutation or reduced JPH2/RyR2 ratios can promote SR Ca(2+) leak and atrial arrhythmias, representing a potential novel therapeutic target for AF.
本研究旨在探讨连接蛋白-2（JPH2）在心房颤动（AF）中的作用。
JPH2 被认为在肌浆网（SR）Ca²⁺处理和兰尼碱受体 Ca²⁺通道（RyR2）调节中发挥重要作用。虽然 RyR2 介导的 Ca²⁺释放功能障碍导致 AF 的发病机制，但关于 JPH2 在心房性心律失常中的潜在作用尚不清楚。
对 203 名无关的肥厚型心肌病患者进行筛查，在 2 名青少年起病阵发性 AF（pAF）患者中发现了一种新型 JPH2 错义突变（E169K）。生成假敲入（PKI）小鼠模型，以确定该 JPH2 突变导致 AF 发展的分子缺陷。
表达 E169K 突变 JPH2 的 PKI 小鼠比野生型（WT）-PKI 小鼠更容易发生可诱导的 AF，而表达与心房性心律失常无关的肥厚型心肌病相关 JPH2 突变（A399S）的 PKI 小鼠与 WT-PKI 小鼠无显著差异。E169K-PKI 而非 A399A-PKI 心房肌细胞显示出更高比例的异常 SR Ca²⁺释放事件。这些变化归因于 E169K-JPH2 与 RyR2 的结合减少。WT-JPH2 转基因、非转基因和 JPH2 敲低小鼠的心房 JPH2 水平与起搏诱导的 AF 发生率呈负相关。从 JPH2 敲低小鼠分离的单个 RyR2 通道的 Ca²⁺火花频率和开放概率明显降低，使用小 JPH2 模拟寡肽。此外，与窦性心律患者相比，pAF 患者的心房 JPH2 水平/每个 RyR2 通道减少，并且自发性 Ca²⁺释放事件的频率增加。
我们的数据表明，由于功能丧失突变或 JPH2/RyR2 比值降低导致 JPH2 介导的 RyR2 稳定性降低，可通过促进 SR Ca²⁺渗漏和心房性心律失常来发挥新的作用，这代表了 AF 的潜在新治疗靶点。
