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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} (C.W.W.); jlederer{at} (W.J.L.)

Microtubule binding distinguishes dystrophin from utrophin.
J. J. Belanto, T. L. Mader, M. D. Eckhoff, D. M. Strandjord, G. B. Banks, M. K. Gardner, D. A. Lowe, and J. M. Ervasti (2014)
PNAS 111, 5723-5728
   Abstract »    Full Text »    PDF »
Mechano-Chemo Transduction Tunes the Heartstrings.
B. L. Prosser and C. W. Ward (2014)
Science Signaling 7, pe7
   Abstract »    Full Text »    PDF »
Mechanochemotransduction During Cardiomyocyte Contraction Is Mediated by Localized Nitric Oxide Signaling.
Z. Jian, H. Han, T. Zhang, J. Puglisi, L. T. Izu, J. A. Shaw, E. Onofiok, J. R. Erickson, Y.-J. Chen, B. Horvath, et al. (2014)
Science Signaling 7, ra27
   Abstract »    Full Text »    PDF »
Hyperactive Adverse Mechanical Stress Responses in Dystrophic Heart Are Coupled to Transient Receptor Potential Canonical 6 and Blocked by cGMP-Protein Kinase G Modulation.
K. Seo, P. P. Rainer, D.-i. Lee, S. Hao, D. Bedja, L. Birnbaumer, O. H. Cingolani, and D. A. Kass (2014)
Circ. Res. 114, 823-832
   Abstract »    Full Text »    PDF »
A new method to detect rapid oxygen changes around cells: How quickly do calcium channels sense oxygen in cardiomyocytes?.
J. A. Scaringi, A. O. Rosa, M. Morad, and L. Cleemann (2013)
J Appl Physiol 115, 1855-1861
   Abstract »    Full Text »    PDF »
Selective Modulation of Coupled Ryanodine Receptors During Microdomain Activation of Calcium/Calmodulin-Dependent Kinase II in the Dyadic Cleft.
E. Dries, V. Bito, I. Lenaerts, G. Antoons, K. R. Sipido, and N. Macquaide (2013)
Circ. Res. 113, 1242-1252
   Abstract »    Full Text »    PDF »
Reactive oxygen species generation is not different during isometric and lengthening contractions of mouse muscle.
D. D. Sloboda and S. V. Brooks (2013)
Am J Physiol Regulatory Integrative Comp Physiol 305, R832-R839
   Abstract »    Full Text »    PDF »
The kinase domains of obscurin interact with intercellular adhesion proteins.
L.-Y. R. Hu and A. Kontrogianni-Konstantopoulos (2013)
FASEB J 27, 2001-2012
   Abstract »    Full Text »    PDF »
ROS regulation of microdomain Ca2+ signalling at the dyads.
H. Zhang, A. M. Gomez, X. Wang, Y. Yan, M. Zheng, and H. Cheng (2013)
Cardiovasc Res 98, 248-258
   Abstract »    Full Text »    PDF »
Calcium release microdomains and mitochondria.
M. Kohlhaas and C. Maack (2013)
Cardiovasc Res 98, 259-268
   Abstract »    Full Text »    PDF »
X-ROS signalling is enhanced and graded by cyclic cardiomyocyte stretch.
B. L. Prosser, C. W. Ward, and W. J. Lederer (2013)
Cardiovasc Res 98, 307-314
   Abstract »    Full Text »    PDF »
Broad Suppression of NADPH Oxidase Activity Exacerbates Ischemia/Reperfusion Injury Through Inadvertent Downregulation of Hypoxia-inducible Factor-1{alpha} and Upregulation of Peroxisome Proliferator-activated Receptor-{alpha}.
S. Matsushima, J. Kuroda, T. Ago, P. Zhai, Y. Ikeda, S. Oka, G.-H. Fong, R. Tian, and J. Sadoshima (2013)
Circ. Res. 112, 1135-1149
   Abstract »    Full Text »    PDF »
A 28-kDa Splice Variant of NADPH Oxidase-4 Is Nuclear-Localized and Involved in Redox Signaling in Vascular Cells.
N. Anilkumar, G. S. Jose, I. Sawyer, C. X. C. Santos, C. Sand, A. C. Brewer, D. Warren, and A. M. Shah (2013)
Arterioscler Thromb Vasc Biol 33, e104-e112
   Abstract »    Full Text »    PDF »
Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria.
C. R. Frasier, F. Moukdar, H. D. Patel, R. C. Sloan, L. M. Stewart, R. J. Alleman, J. D. La Favor, and D. A. Brown (2013)
Cardiovasc Res 98, 47-55
   Abstract »    Full Text »    PDF »
Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy.
S. Kyrychenko, E. Polakova, C. Kang, K. Pocsai, N. D. Ullrich, E. Niggli, and N. Shirokova (2013)
Cardiovasc Res 97, 666-675
   Abstract »    Full Text »    PDF »
AMPK attenuates microtubule proliferation in cardiac hypertrophy.
J. T. Fassett, X. Hu, X. Xu, Z. Lu, P. Zhang, Y. Chen, and R. J. Bache (2013)
Am J Physiol Heart Circ Physiol 304, H749-H758
   Abstract »    Full Text »    PDF »
Superoxide Triggers an Acid Burst in Saccharomyces cerevisiae to Condition the Environment of Glucose-starved Cells.
J. A. Baron, K. M. Laws, J. S. Chen, and V. C. Culotta (2013)
J. Biol. Chem. 288, 4557-4566
   Abstract »    Full Text »    PDF »
The Anrep effect: 100 years later.
H. E. Cingolani, N. G. Perez, O. H. Cingolani, and I. L. Ennis (2013)
Am J Physiol Heart Circ Physiol 304, H175-H182
   Abstract »    Full Text »    PDF »
Evidence for stress-dependent mechanoreceptors linking intestinal biomechanics and sensory signal transduction.
H. Gregersen, W. Jiang, D. Liao, and D. Grundy (2013)
Exp Physiol 98, 123-133
   Abstract »    Full Text »    PDF »
Heart failure highlights in 2011.
B. D. Westenbrink, K. Damman, M. Rienstra, A. H. Maass, and P. van der Meer (2012)
Eur J Heart Fail 14, 1090-1096
   Abstract »    Full Text »    PDF »
Redox Signaling in Cardiac Physiology and Pathology.
J. R. Burgoyne, H. Mongue-Din, P. Eaton, and A. M. Shah (2012)
Circ. Res. 111, 1091-1106
   Abstract »    Full Text »    PDF »
Activation of Neuronal NMDA Receptors Induces Superoxide-Mediated Oxidative Stress in Neighboring Neurons and Astrocytes.
R. C. Reyes, A. M. Brennan, Y. Shen, Y. Baldwin, and R. A. Swanson (2012)
J. Neurosci. 32, 12973-12978
   Abstract »    Full Text »    PDF »
Focal but reversible diastolic sheet dysfunction reflects regional calcium mishandling in dystrophic mdx mouse hearts.
Y.-J. Cheng, D. Lang, S. D. Caruthers, I. R. Efimov, J. Chen, and S. A. Wickline (2012)
Am J Physiol Heart Circ Physiol 303, H559-H568
   Abstract »    Full Text »    PDF »
Hypoxic regulation of cardiac Ca2+ channel: possible role of haem oxygenase.
A. O. Rosa, S. Movafagh, L. Cleemann, and M. Morad (2012)
J. Physiol. 590, 4223-4237
   Abstract »    Full Text »    PDF »
Could Plugging the Oxidation-Mediated Ca2+ Leak Stem the Tide of the Atrial Fibrillation Epidemic?.
P. H. Backx (2012)
Circ. Res. 111, 662-665
   Full Text »    PDF »
Science Signaling Podcast: 7 August 2012.
C. W. Ward, R. J. Khairallah, E. P. Hoffman, and A. M. VanHook (2012)
Science Signaling 5, pc18
   Abstract »    Full Text »
Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy.
R. J. Khairallah, G. Shi, F. Sbrana, B. L. Prosser, C. Borroto, M. J. Mazaitis, E. P. Hoffman, A. Mahurkar, F. Sachs, Y. Sun, et al. (2012)
Science Signaling 5, ra56
   Abstract »    Full Text »    PDF »
NOX2-dependent ROS is required for HDAC5 nuclear efflux and contributes to HDAC4 nuclear efflux during intense repetitive activity of fast skeletal muscle fibers.
Y. Liu, E. O. Hernandez-Ochoa, W. R. Randall, and M. F. Schneider (2012)
Am J Physiol Cell Physiol 303, C334-C347
   Abstract »    Full Text »    PDF »
Cooperative coupling of cell-matrix and cell-cell adhesions in cardiac muscle.
M. L. McCain, H. Lee, Y. Aratyn-Schaus, A. G. Kleber, and K. K. Parker (2012)
PNAS 109, 9881-9886
   Abstract »    Full Text »    PDF »
Superresolution Subspace Signaling.
W. J. Lederer, B. M. Hagen, and G. Zhao (2012)
Science 336, 546-547
   Abstract »    Full Text »    PDF »
Getting to the Heart of Mechanotransduction.
C. Hidalgo and P. Donoso (2011)
Science 333, 1388-1390
   Abstract »    Full Text »    PDF »

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