title: Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling.
abstract: Cardiomyocytes contract against a mechanical load during each heartbeat, and excessive mechanical stress leads to heart diseases. Using a cell-in-gel system that imposes an afterload during cardiomyocyte contraction, we found that nitric oxide synthase (NOS) was involved in transducing mechanical load to alter Ca(2+) dynamics. In mouse ventricular myocytes, afterload increased the systolic Ca(2+) transient, which enhanced contractility to counter mechanical load but also caused spontaneous Ca(2+) sparks during diastole that could be arrhythmogenic. The increases in the Ca(2+) transient and sparks were attributable to increased ryanodine receptor (RyR) sensitivity because the amount of Ca2(+) in the sarcoplasmic reticulum load was unchanged. Either pharmacological inhibition or genetic deletion of nNOS (or NOS1), but not of eNOS (or NOS3), prevented afterload-induced Ca2(+) sparks. This differential effect may arise from localized NO signaling, arising from the proximity of nNOS to RyR, as determined by super-resolution imaging. Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) also contributed to afterload-induced Ca(2+) sparks. Cardiomyocytes from a mouse model of familial hypertrophic cardiomyopathy exhibited enhanced mechanotransduction and frequent arrhythmogenic Ca(2+) sparks. Inhibiting nNOS and CaMKII, but not NOX2, in cardiomyocytes from this model eliminated the Ca2(+) sparks, suggesting mechanotransduction activated nNOS and CaMKII independently from NOX2. Thus, our data identify nNOS, CaMKII, and NOX2 as key mediators in mechanochemotransduction during cardiac contraction, which provides new therapeutic targets for treating mechanical stress-induced Ca(2+) dysregulation, arrhythmias, and cardiomyopathy.
authors.affiliation: 1Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Jian
authors.forename: Huilan
authors.initials: H
authors.lastname: Han
authors.forename: Tieqiao
authors.initials: T
authors.lastname: Zhang
authors.forename: Jose
authors.initials: J
authors.lastname: Puglisi
authors.forename: Leighton T
authors.initials: LT
authors.lastname: Izu
authors.forename: John A
authors.initials: JA
authors.lastname: Shaw
authors.forename: Ekama
authors.initials: E
authors.lastname: Onofiok
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Erickson
authors.forename: Yi-Je
authors.initials: YJ
authors.lastname: Chen
authors.forename: Balazs
authors.initials: B
authors.lastname: Horvath
authors.forename: Rafael
authors.initials: R
authors.lastname: Shimkunas
authors.forename: Wenwu
authors.initials: W
authors.lastname: Xiao
authors.forename: Yuanpei
authors.initials: Y
authors.lastname: Li
authors.forename: Tingrui
authors.initials: T
authors.lastname: Pan
authors.forename: James
authors.initials: J
authors.lastname: Chan
authors.forename: Tamas
authors.initials: T
authors.lastname: Banyasz
authors.forename: Jil C
authors.initials: JC
authors.lastname: Tardiff
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen-Izu
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003971:Diastole; D006321:Heart / Q000502:physiology; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015398:Signal Transduction; D013599:Systole
chemical_list: D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2