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

Science, 9 September 2011
Vol. 333, Issue 6048, p. 1440-1445
DOI: 10.1126/science.1202768

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

  1. Benjamin L. Prosser1,
  2. Christopher W. Ward2,*,
  3. W. J. Lederer1,*
  1. 1Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine, Baltimore, MD 21209, USA.
  2. 2School of Nursing, University of Maryland, Baltimore, MD 21209, USA.
  1. *To whom correspondence should be addressed. E-mail: ward{at}son.umaryland.edu (C.W.W.); jlederer{at}umaryland.edu (W.J.L.)

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.

  • Received for publication 11 January 2011.
  • Accepted for publication 18 July 2011.

Citation:

B. L. Prosser, C. W. Ward, and W. J. Lederer, X-ROS Signaling: Rapid Mechano-Chemo Transduction in Heart. Science 333, 1440-1445 (2011).

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