Department of Pharmacology, Physiology and Neuroscience and.
Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.
JCI Insight. 2019 Dec 19;4(24):130091. doi: 10.1172/jci.insight.130091.
Patients with Duchenne muscular dystrophy (DMD) commonly present with severe ventricular arrhythmias that contribute to heart failure. Arrhythmias and lethality are also consistently observed in adult Dmdmdx mice, a mouse model of DMD, after acute β-adrenergic stimulation. These pathological features were previously linked to aberrant expression and remodeling of the cardiac gap junction protein connexin43 (Cx43). Here, we report that remodeled Cx43 protein forms Cx43 hemichannels in the lateral membrane of Dmdmdx cardiomyocytes and that the β-adrenergic agonist isoproterenol (Iso) aberrantly activates these hemichannels. Block of Cx43 hemichannels or a reduction in Cx43 levels (using Dmdmdx Cx43+/- mice) prevents the abnormal increase in membrane permeability, plasma membrane depolarization, and Iso-evoked electrical activity in these cells. Additionally, Iso treatment promotes nitric oxide (NO) production and S-nitrosylation of Cx43 hemichannels in Dmdmdx heart. Importantly, inhibition of NO production prevents arrhythmias evoked by Iso. We found that NO directly activates Cx43 hemichannels by S-nitrosylation of cysteine at position 271. Our results demonstrate that opening of remodeled and S-nitrosylated Cx43 hemichannels plays a key role in the development of arrhythmias in DMD mice and that these channels may serve as therapeutic targets to prevent fatal arrhythmias in patients with DMD .
杜氏肌营养不良症（DMD）患者常出现严重的室性心律失常，导致心力衰竭。在 DMD 的小鼠模型 Dmdmdx 中，急性β-肾上腺素能刺激后，也会持续观察到心律失常和致死性。这些病理特征以前与心脏缝隙连接蛋白 connexin43（Cx43）的异常表达和重构有关。在这里，我们报告重构的 Cx43 蛋白在 Dmdmdx 心肌细胞的侧膜中形成 Cx43 半通道，并且β-肾上腺素能激动剂异丙肾上腺素（Iso）异常激活这些半通道。阻断 Cx43 半通道或降低 Cx43 水平（使用 Dmdmdx Cx43+/- 小鼠）可防止这些细胞中膜通透性、质膜去极化和 Iso 诱发的电活性的异常增加。此外，Iso 处理可促进 Dmdmdx 心脏中一氧化氮（NO）的产生和 Cx43 半通道的 S-亚硝基化。重要的是，NO 产生的抑制可防止 Iso 诱发的心律失常。我们发现，NO 通过半胱氨酸第 271 位的 S-亚硝基化直接激活 Cx43 半通道。我们的结果表明，重构和 S-亚硝基化的 Cx43 半通道的开放在 DMD 小鼠心律失常的发展中起关键作用，并且这些通道可能作为治疗靶点，以防止 DMD 患者的致命性心律失常。
