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Science 333 (6048): 1440-1445

Copyright © 2011 by the American Association for the Advancement of Science

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

Benjamin L. Prosser,1 Christopher W. Ward,2,* W. J. Lederer1,*

Abstract: 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.

1 Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine, Baltimore, MD 21209, USA.
2 School of Nursing, University of Maryland, Baltimore, MD 21209, USA.

* To whom correspondence should be addressed. E-mail: ward{at}son.umaryland.edu (C.W.W.); jlederer{at}umaryland.edu (W.J.L.)

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