Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]

Publication Date:
2018-03-16
Publisher:
American Heart Association (AHA)
Print ISSN:
0009-7330
Electronic ISSN:
1524-4571
Topics:
Medicine
Keywords:
Electrophysiology, Atrial Fibrillation, Calcium Cycling/Excitation-Contraction Coupling, Cell Signaling/Signal Transduction, Aging
Published by:
http://www.americanheart.org/
_version_ 1836398847755026432
autor Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
beschreibung 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.
citation_standardnr 6208004
datenlieferant ipn_articles
feed_id 321
feed_publisher American Heart Association (AHA)
feed_publisher_url http://www.americanheart.org/
insertion_date 2018-03-16
journaleissn 1524-4571
journalissn 0009-7330
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher American Heart Association (AHA)
quelle Circulation Research
relation http://circres.ahajournals.org/content/122/6/821.short?rss=1
schlagwort Electrophysiology, Atrial Fibrillation, Calcium Cycling/Excitation-Contraction Coupling, Cell Signaling/Signal Transduction, Aging
search_space articles
shingle_author_1 Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
shingle_author_2 Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
shingle_author_3 Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
shingle_author_4 Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
shingle_catch_all_1 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
Electrophysiology, Atrial Fibrillation, Calcium Cycling/Excitation-Contraction Coupling, Cell Signaling/Signal Transduction, Aging
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.
Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
American Heart Association (AHA)
0009-7330
00097330
1524-4571
15244571
shingle_catch_all_2 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
Electrophysiology, Atrial Fibrillation, Calcium Cycling/Excitation-Contraction Coupling, Cell Signaling/Signal Transduction, Aging
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.
Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
American Heart Association (AHA)
0009-7330
00097330
1524-4571
15244571
shingle_catch_all_3 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
Electrophysiology, Atrial Fibrillation, Calcium Cycling/Excitation-Contraction Coupling, Cell Signaling/Signal Transduction, Aging
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.
Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
American Heart Association (AHA)
0009-7330
00097330
1524-4571
15244571
shingle_catch_all_4 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
Electrophysiology, Atrial Fibrillation, Calcium Cycling/Excitation-Contraction Coupling, Cell Signaling/Signal Transduction, Aging
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.
Jiajie Yan, Weiwei Zhao, Justin K. Thomson, Xianlong Gao, Dominic M. De; Marco, Elena Carrillo, Biyi Chen, Xiaomin Wu, Kenneth S. Ginsburg, Mamdouh Bakhos, Donald M. Bers, Mark E. Anderson, Long-Sheng Song, Michael Fill, Xun Ai
American Heart Association (AHA)
0009-7330
00097330
1524-4571
15244571
shingle_title_1 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
shingle_title_2 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
shingle_title_3 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
shingle_title_4 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
timestamp 2025-06-30T23:33:35.037Z
titel Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
titel_suche Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial ArrhythmogenesisNovelty and Significance [Cellular Biology]
topic WW-YZ
uid ipn_articles_6208004