X-ROS Signaling: Rapid Mechano-Chemo Transduction in Heart.

We report that in heart cells, physiologic stretch rapidly activates reduced-form nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (N0X2) 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 N0X2 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. [ABSTRACT FROM AUTHOR]