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 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism
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Calcium Signaling
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Electric Stimulation
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Mechanotransduction, Cellular*
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred mdx
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Microtubules / metabolism
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Muscular Dystrophy, Animal / metabolism
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Muscular Dystrophy, Animal / physiopathology
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Myocardial Contraction
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Myocytes, Cardiac / metabolism
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Myocytes, Cardiac / physiology*
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NADPH Oxidase 2
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NADPH Oxidases / antagonists & inhibitors
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NADPH Oxidases / metabolism*
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Oxidation-Reduction
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism*
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Ryanodine Receptor Calcium Release Channel / metabolism
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Sarcolemma / metabolism
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Sarcoplasmic Reticulum / metabolism
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Signal Transduction
Substances
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Membrane Glycoproteins
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Reactive Oxygen Species
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Ryanodine Receptor Calcium Release Channel
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Cybb protein, mouse
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Cybb protein, rat
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NADPH Oxidase 2
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NADPH Oxidases
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Calcium