TY - JOUR
T1 - Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling
AU - Jian, Zhong
AU - Han, Huilan
AU - Zhang, Tieqiao
AU - Puglisi, Jose
AU - Izu, Leighton T.
AU - Shaw, John A.
AU - Onofiok, Ekama
AU - Erickson, Jeffery R.
AU - Chen, Yi Je
AU - Horvath, Balazs
AU - Shimkunas, Rafael
AU - Xiao, Wenwu
AU - Li, Yuanpei
AU - Pan, Tingrui
AU - Chan, James
AU - Banyasz, Tamas
AU - Tardiff, Jil C.
AU - Chiamvimonvat, Nipavan
AU - Bers, Donald M.
AU - Lam, Kit S.
AU - Chen-Izu, Ye
PY - 2014/3/18
Y1 - 2014/3/18
N2 - 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 Ca2+ dynamics. In mouse ventricular myocytes, afterload increased the systolic Ca2+ transient, which enhanced contractility to counter mechanical load, but also caused spontaneous Ca2+ 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, 4as determined by super-resolution imaging. Ca2+-calmodulin-dependent protein kinase II (CaMKII) and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) also contributed to afterload-induced Ca2+ sparks. Cardiomyocytes from amousemodel of familial hypertrophic cardiomyopathy exhibited enhanced mechanotransduction and frequent arrhythmogenic Ca 2+ sparks. Inhibiting nNOS and CaMKII, but not NOX2, in cardiomyocytes from thismodel 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 Ca2+ dysregulation, arrhythmias, and cardiomyopathy.
AB - 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 Ca2+ dynamics. In mouse ventricular myocytes, afterload increased the systolic Ca2+ transient, which enhanced contractility to counter mechanical load, but also caused spontaneous Ca2+ 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, 4as determined by super-resolution imaging. Ca2+-calmodulin-dependent protein kinase II (CaMKII) and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) also contributed to afterload-induced Ca2+ sparks. Cardiomyocytes from amousemodel of familial hypertrophic cardiomyopathy exhibited enhanced mechanotransduction and frequent arrhythmogenic Ca 2+ sparks. Inhibiting nNOS and CaMKII, but not NOX2, in cardiomyocytes from thismodel 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 Ca2+ dysregulation, arrhythmias, and cardiomyopathy.
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UR - http://www.scopus.com/inward/citedby.url?scp=84897133718&partnerID=8YFLogxK
U2 - 10.1126/scisignal.2005046
DO - 10.1126/scisignal.2005046
M3 - Article
C2 - 24643800
AN - SCOPUS:84897133718
SN - 1937-9145
VL - 7
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
IS - 317
M1 - ra27
ER -