Journal article
Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis
Circulation research, Vol.122(6), pp.821-835
03/16/2018
DOI: 10.1161/CIRCRESAHA.117.312536
PMCID: PMC5924593
PMID: 29352041
Abstract
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.
To explore the functional role of an important stress response JNK (c-Jun N-terminal kinase) in sarcoplasmic reticulum Ca
handling and consequently Ca
-mediated atrial arrhythmias.
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 (Ca
/calmodulin-dependent kinase II), and sarcoplasmic reticulum Ca
release RyR2 (ryanodine receptor) channels. JNK2 activates CaMKII, a critical proarrhythmic molecule in cardiac muscle. In turn, activated CaMKII upregulates diastolic sarcoplasmic reticulum Ca
leak mediated by RyR2 channels. This leads to aberrant intracellular Ca
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.
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.
Details
- Title: Subtitle
- Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis
- Creators
- Jiajie Yan - Rush UniversityWeiwei Zhao - Rush UniversityJustin K Thomson - Department of Cell and Molecular PhysiologyXianlong Gao - Department of Cell and Molecular PhysiologyDominic M DeMarco - Rush UniversityElena Carrillo - Rush UniversityBiyi Chen - University of IowaXiaomin Wu - Department of Cell and Molecular PhysiologyKenneth S Ginsburg - University of California, DavisMamdouh Bakhos - Loyola University ChicagoDonald M Bers - University of California, DavisMark E Anderson - Johns Hopkins MedicineLong-Sheng Song - University of IowaMichael Fill - Rush UniversityXun Ai - Rush University
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.122(6), pp.821-835
- DOI
- 10.1161/CIRCRESAHA.117.312536
- PMID
- 29352041
- PMCID
- PMC5924593
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- R01 HL071140 / NHLBI NIH HHS R01 HL079031 / NHLBI NIH HHS R01 HL092097 / NHLBI NIH HHS R01 HL070250 / NHLBI NIH HHS R01 AA024769 / NIAAA NIH HHS R01 HL113640 / NHLBI NIH HHS R01 HL130346 / NHLBI NIH HHS P01 HL080101 / NHLBI NIH HHS P01 HL062426 / NHLBI NIH HHS R01 HL057832 / NHLBI NIH HHS R01 AR054098 / NIAMS NIH HHS R01 HL096652 / NHLBI NIH HHS R56 HL071140 / NHLBI NIH HHS R01 HL090905 / NHLBI NIH HHS R01 HL030077 / NHLBI NIH HHS I01 BX002334 / BLRD VA R01 HL105242 / NHLBI NIH HHS
- Language
- English
- Date published
- 03/16/2018
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984293077502771
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