Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling

Zhong Jian, Huilan Han, Tieqiao Zhang, Jose Puglisi, Leighton T Izu, John A. Shaw, Ekama Onofiok, Jeffery R. Erickson, Yi-Je Chen, Balazs Horvath, Rafael Shimkunas, Wenwu Xiao, Yuanpei Li, Tingrui Pan, James W Chan, Tamas Banyasz, Jil C. Tardiff, Nipavan Chiamvimonvat, Donald M Bers, Kit Lam & 1 others Ye Chen-Izu

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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 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.

Original languageEnglish (US)
Article numberra27
JournalScience Signaling
Volume7
Issue number317
DOIs
StatePublished - Mar 18 2014

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Electric sparks
Cardiac Myocytes
Nitric Oxide
Ryanodine Receptor Calcium Release Channel
Mechanical Stress
Familial Hypertrophic Cardiomyopathy
Diastole
Sarcoplasmic Reticulum
Cardiomyopathies
NADP
Nitric Oxide Synthase
Muscle Cells
Cardiac Arrhythmias
Heart Diseases
Oxidoreductases
Gels
Pharmacology
Loads (forces)
Imaging techniques

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling. / Jian, Zhong; Han, Huilan; Zhang, Tieqiao; Puglisi, Jose; Izu, Leighton T; Shaw, John A.; Onofiok, Ekama; Erickson, Jeffery R.; Chen, Yi-Je; Horvath, Balazs; Shimkunas, Rafael; Xiao, Wenwu; Li, Yuanpei; Pan, Tingrui; Chan, James W; Banyasz, Tamas; Tardiff, Jil C.; Chiamvimonvat, Nipavan; Bers, Donald M; Lam, Kit; Chen-Izu, Ye.

In: Science Signaling, Vol. 7, No. 317, ra27, 18.03.2014.

Research output: Contribution to journalArticle

Jian, Zhong ; Han, Huilan ; Zhang, Tieqiao ; Puglisi, Jose ; Izu, Leighton T ; Shaw, John A. ; Onofiok, Ekama ; Erickson, Jeffery R. ; Chen, Yi-Je ; Horvath, Balazs ; Shimkunas, Rafael ; Xiao, Wenwu ; Li, Yuanpei ; Pan, Tingrui ; Chan, James W ; Banyasz, Tamas ; Tardiff, Jil C. ; Chiamvimonvat, Nipavan ; Bers, Donald M ; Lam, Kit ; Chen-Izu, Ye. / Mechanochemotransduction during cardiomyocyte contraction is mediated by localized nitric oxide signaling. In: Science Signaling. 2014 ; Vol. 7, No. 317.
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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 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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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 W

AU - Banyasz, Tamas

AU - Tardiff, Jil C.

AU - Chiamvimonvat, Nipavan

AU - Bers, Donald M

AU - Lam, Kit

AU - Chen-Izu, Ye

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