title: X-ROS signaling: rapid mechano-chemo transduction in heart.
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.
authors: Center for Biomedical Engineering and Technology (BioMET), University of Maryland School of Medicine, Baltimore, MD 21209, USA.
authors: Benjamin L
authors: BL
authors: Prosser
authors: Christopher W
authors: CW
authors: Ward
authors: W J
authors: WJ
authors: Lederer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D004558:Electric Stimulation; D040542:Mechanotransduction, Cellular; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008870:Microtubules / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000503:physiopathology; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; C488842:Cybb protein, mouse; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002118:Calcium