Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis

Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. DeMarco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S Ginsburg, Mamdouh Bakhos, Donald M Bers, Mark E. Anderson, Long Sheng Song, Michael Fill, Xun Ai

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Rationale: Atrial fibrillation (AF) is the most common arrhythmia, and advanced age is an inevitable and predominant AF risk factor. However, the mechanisms that couple aging and AF propensity remain unclear, making targeted therapeutic interventions unattainable. Objective: To explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca2+ handling and consequently Ca2+-mediated atrial arrhythmias. Methods and Results: We used a series of cutting-edge electrophysiological and molecular techniques, exploited the power of transgenic mouse models to detail the molecular mechanism, and verified its clinical applicability in parallel studies on donor human hearts. We discovered that significantly increased activity of the stress response kinase JNK2 (JNK isoform 2) in the aged atria is involved in arrhythmic remodeling. The JNK-driven atrial proarrhythmic mechanism is supported by a pathway linking JNK, CaMKII (Ca2+/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca2+ release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca2+ leak mediated by RyR2 channels. This leads to aberrant intracellular Ca2+ waves and enhanced AF propensity. In contrast, this mechanism is absent in young atria. In JNK challenged animal models, this is eliminated by JNK2 ablation or CaMKII inhibition. Conclusions: We have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.

Original languageEnglish (US)
Pages (from-to)821-835
Number of pages15
JournalCirculation Research
Volume122
Issue number6
DOIs
StatePublished - Mar 1 2018

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinases
Atrial Fibrillation
JNK Mitogen-Activated Protein Kinases
Protein Isoforms
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Cardiac Arrhythmias
Phosphotransferases
Mitogen-Activated Protein Kinase 9
Atrial Remodeling
Transgenic Mice
Myocardium
Up-Regulation
Animal Models
Therapeutics

Keywords

  • Aged
  • Atrial fibrillation
  • Calcium-calmodulin-dependent protein kinase type 2
  • Phosphorylation
  • Ryanodine receptor 2
  • Sarcoplasmic reticulum
  • Stress-activated protein kinase JNK2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Yan, J., Zhao, W., Thomson, J. K., Gao, X., DeMarco, D. M., Carrillo, E., ... Ai, X. (2018). Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis. Circulation Research, 122(6), 821-835. https://doi.org/10.1161/CIRCRESAHA.117.312536

Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis. / Yan, Jiajie; Zhao, Weiwei; Thomson, Justin K.; Gao, Xianlong; DeMarco, Dominic M.; Carrillo, Elena; Chen, Biyi; Wu, Xiaomin; Ginsburg, Kenneth S; Bakhos, Mamdouh; Bers, Donald M; Anderson, Mark E.; Song, Long Sheng; Fill, Michael; Ai, Xun.

In: Circulation Research, Vol. 122, No. 6, 01.03.2018, p. 821-835.

Research output: Contribution to journalArticle

Yan, J, Zhao, W, Thomson, JK, Gao, X, DeMarco, DM, Carrillo, E, Chen, B, Wu, X, Ginsburg, KS, Bakhos, M, Bers, DM, Anderson, ME, Song, LS, Fill, M & Ai, X 2018, 'Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis', Circulation Research, vol. 122, no. 6, pp. 821-835. https://doi.org/10.1161/CIRCRESAHA.117.312536
Yan, Jiajie ; Zhao, Weiwei ; Thomson, Justin K. ; Gao, Xianlong ; DeMarco, Dominic M. ; Carrillo, Elena ; Chen, Biyi ; Wu, Xiaomin ; Ginsburg, Kenneth S ; Bakhos, Mamdouh ; Bers, Donald M ; Anderson, Mark E. ; Song, Long Sheng ; Fill, Michael ; Ai, Xun. / Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis. In: Circulation Research. 2018 ; Vol. 122, No. 6. pp. 821-835.
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abstract = "Rationale: Atrial fibrillation (AF) is the most common arrhythmia, and advanced age is an inevitable and predominant AF risk factor. However, the mechanisms that couple aging and AF propensity remain unclear, making targeted therapeutic interventions unattainable. Objective: To explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca2+ handling and consequently Ca2+-mediated atrial arrhythmias. Methods and Results: We used a series of cutting-edge electrophysiological and molecular techniques, exploited the power of transgenic mouse models to detail the molecular mechanism, and verified its clinical applicability in parallel studies on donor human hearts. We discovered that significantly increased activity of the stress response kinase JNK2 (JNK isoform 2) in the aged atria is involved in arrhythmic remodeling. The JNK-driven atrial proarrhythmic mechanism is supported by a pathway linking JNK, CaMKII (Ca2+/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca2+ release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca2+ leak mediated by RyR2 channels. This leads to aberrant intracellular Ca2+ waves and enhanced AF propensity. In contrast, this mechanism is absent in young atria. In JNK challenged animal models, this is eliminated by JNK2 ablation or CaMKII inhibition. Conclusions: We have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.",
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AU - Zhao, Weiwei

AU - Thomson, Justin K.

AU - Gao, Xianlong

AU - DeMarco, Dominic M.

AU - Carrillo, Elena

AU - Chen, Biyi

AU - Wu, Xiaomin

AU - Ginsburg, Kenneth S

AU - Bakhos, Mamdouh

AU - Bers, Donald M

AU - Anderson, Mark E.

AU - Song, Long Sheng

AU - Fill, Michael

AU - Ai, Xun

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N2 - Rationale: Atrial fibrillation (AF) is the most common arrhythmia, and advanced age is an inevitable and predominant AF risk factor. However, the mechanisms that couple aging and AF propensity remain unclear, making targeted therapeutic interventions unattainable. Objective: To explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca2+ handling and consequently Ca2+-mediated atrial arrhythmias. Methods and Results: We used a series of cutting-edge electrophysiological and molecular techniques, exploited the power of transgenic mouse models to detail the molecular mechanism, and verified its clinical applicability in parallel studies on donor human hearts. We discovered that significantly increased activity of the stress response kinase JNK2 (JNK isoform 2) in the aged atria is involved in arrhythmic remodeling. The JNK-driven atrial proarrhythmic mechanism is supported by a pathway linking JNK, CaMKII (Ca2+/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca2+ release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca2+ leak mediated by RyR2 channels. This leads to aberrant intracellular Ca2+ waves and enhanced AF propensity. In contrast, this mechanism is absent in young atria. In JNK challenged animal models, this is eliminated by JNK2 ablation or CaMKII inhibition. Conclusions: We have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.

AB - Rationale: Atrial fibrillation (AF) is the most common arrhythmia, and advanced age is an inevitable and predominant AF risk factor. However, the mechanisms that couple aging and AF propensity remain unclear, making targeted therapeutic interventions unattainable. Objective: To explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca2+ handling and consequently Ca2+-mediated atrial arrhythmias. Methods and Results: We used a series of cutting-edge electrophysiological and molecular techniques, exploited the power of transgenic mouse models to detail the molecular mechanism, and verified its clinical applicability in parallel studies on donor human hearts. We discovered that significantly increased activity of the stress response kinase JNK2 (JNK isoform 2) in the aged atria is involved in arrhythmic remodeling. The JNK-driven atrial proarrhythmic mechanism is supported by a pathway linking JNK, CaMKII (Ca2+/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca2+ release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca2+ leak mediated by RyR2 channels. This leads to aberrant intracellular Ca2+ waves and enhanced AF propensity. In contrast, this mechanism is absent in young atria. In JNK challenged animal models, this is eliminated by JNK2 ablation or CaMKII inhibition. Conclusions: We have identified JNK2-driven CaMKII activation as a novel mode of kinase crosstalk and a causal factor in atrial arrhythmic remodeling, making JNK2 a compelling new therapeutic target for AF prevention and treatment.

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