Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine, Baltimore, MD 21209, USA.
Science. 2011 Sep 9;333(6048):1440-5. doi: 10.1126/science.1202768.
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 Ca(2+) sparks, the elementary Ca(2+) release events in heart. Although this stretch-dependent "tuning" of RyRs increases Ca(2+) signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca(2+) sparks to trigger arrhythmogenic Ca(2+) waves. In the mouse model of Duchenne muscular dystrophy, hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca(2+) release from the SR. X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca(2+) release in the heart and offers fresh therapeutic possibilities.
我们报告称，在心脏细胞中，生理性拉伸可迅速激活还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶 2（NOX2），在微管（X-ROS 信号）依赖性过程中产生活性氧（ROS）。ROS 产生于肌膜和 T 管膜，NOX2 位于此处，并使肌浆网（SR）中附近的兰尼碱受体（RyRs）敏化。这会引发 Ca(2+)火花的爆发，即心脏中的基本 Ca(2+)释放事件。尽管这种依赖于拉伸的 RyRs“调谐”增加了健康心肌细胞中 Ca(2+)信号的敏感性，但在疾病中，它使 Ca(2+)火花能够引发心律失常性 Ca(2+)波。在杜氏肌营养不良症的小鼠模型中，过度活跃的 X-ROS 信号通过 SR 中异常的 Ca(2+)释放导致心肌病。因此，X-ROS 信号为心脏中 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。
