X-ROS Signaling: Rapid Mechano-Chemo Transduction in Heart
X-ROS Signaling: Rapid Mechano-Chemo Transduction in Heart
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DOI：
10.1126/science.1202768
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发表时间：
2011-09-09
期刊：
影响因子：
56.9
通讯作者：
Lederer, W. J.
中科院分区：
文献类型：
--
作者：
Prosser, Benjamin L.;Ward, Christopher W.;Lederer, W. J.
我们报告说，在心脏细胞中，生理拉伸迅速激活还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶2（NOX 2），产生活性氧（ROS）的过程中依赖于微管（X-ROS信号）。ROS的产生发生在NOX 2所在的肌膜和t-小管膜中，并使肌浆网（SR）中的兰尼碱受体（RyR）附近敏感。这引发了Ca 2+火花的爆发，心脏中的基本Ca 2+释放事件。尽管RyR的这种牵张依赖性“调谐”增加了健康心肌细胞中的Ca 2+信号传导敏感性，但在疾病中，它使Ca 2+火花能够触发致心律失常的Ca 2+波。在Duchenne肌营养不良症的小鼠模型中，过度活跃的X-ROS信号传导通过SR的异常Ca 2+释放促成心肌病。X-ROS信号传导因此为心脏中Ca 2+释放的机械转导提供了机制解释，并提供了新的治疗可能性。
We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where NOX2 is located and sensitizes nearby ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). This triggers a burst of Ca2+ sparks, the elementary Ca2+ release events in heart. Although this stretch-dependent "tuning" of RyRs increases Ca2+ signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca2+ sparks to trigger arrhythmogenic Ca2+ waves. In the mouse model of Duchenne muscular dystrophy, hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca2+ release from the SR. X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca2+ release in the heart and offers fresh therapeutic possibilities.