Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis

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.

[1]  Sathya D. Unudurthi,et al.  Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling and atrial arrhythmia. , 2020, Heart rhythm.

[2]  D. Terentyev,et al.  Altered Intracellular Calcium Homeostasis and Arrhythmogenesis in the Aged Heart , 2019, International journal of molecular sciences.

[3]  D. V. Van Wagoner,et al.  Plasma endothelin-1 levels are increased in atrial fibrillation patients with hyperthyroidism , 2018, PloS one.

[4]  Xun Ai,et al.  Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia , 2018, Journal of the American College of Cardiology.

[5]  P. Mohler,et al.  Role of CaMKII in cardiac arrhythmias. , 2015, Trends in cardiovascular medicine.

[6]  V. Fast,et al.  Voltage and calcium dual channel optical mapping of cultured HL-1 atrial myocyte monolayer. , 2015, Journal of visualized experiments : JoVE.

[7]  Xun Ai,et al.  Genetic Deletion of Rnd3/RhoE Results in Mouse Heart Calcium Leakage Through Upregulation of Protein Kinase A Signaling , 2015, Circulation research.

[8]  Xun Ai,et al.  Novel Methods of Automated Quantification of Gap Junction Distribution and Interstitial Collagen Quantity from Animal and Human Atrial Tissue Sections , 2014, PloS one.

[9]  D. Bers.  Cardiac sarcoplasmic reticulum calcium leak: basis and roles in cardiac dysfunction. , 2014, Annual review of physiology.

[10]  Na Li,et al.  Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation , 2014, Circulation.

[11]  Michael Fill,et al.  Mechanism of calsequestrin regulation of single cardiac ryanodine receptor in normal and pathological conditions , 2013, The Journal of general physiology.

[12]  V. Fast,et al.  c-Jun N-terminal kinase activation contributes to reduced connexin43 and development of atrial arrhythmias. , 2013, Cardiovascular Research.

[13]  A. Rokita,et al.  New Therapeutic Targets in Cardiology: Arrhythmias and Ca2+/Calmodulin-Dependent Kinase II (CaMKII) , 2012, Circulation.

[14]  Sheng Wei,et al.  In Situ Confocal Imaging in Intact Heart Reveals Stress-Induced Ca2+ Release Variability in a Murine Catecholaminergic Polymorphic Ventricular Tachycardia Model of Type 2 Ryanodine ReceptorR4496C+/− Mutation , 2012, Circulation. Arrhythmia and electrophysiology.

[15]  D. Gillespie,et al.  Ryanodine Receptor Current Amplitude Controls Ca2+ Sparks in Cardiac Muscle , 2012, Circulation research.

[16]  D. Bers,et al.  CaMKIIδC slows [Ca]i decline in cardiac myocytes by promoting Ca sparks. , 2012, Biophysical journal.

[17]  T. Wieland,et al.  Role of RyR2 Phosphorylation at S2814 During Heart Failure Progression , 2012, Circulation research.

[18]  Mark E. Anderson,et al.  Oxidation of CaMKII determines the cardiotoxic effects of aldosterone , 2011, Nature Medicine.

[19]  P. Platonov,et al.  Structural abnormalities in atrial walls are associated with presence and persistency of atrial fibrillation but not with age. , 2011, Journal of the American College of Cardiology.

[20]  D. Bers,et al.  Fluorescence Resonance Energy Transfer–Based Sensor Camui Provides New Insight Into Mechanisms of Calcium/Calmodulin-Dependent Protein Kinase II Activation in Intact Cardiomyocytes , 2011, Circulation research.

[21]  M. Anderson.  Pathways for CaMKII activation in disease. , 2011, Heart rhythm.

[22]  Yibin Wang,et al.  Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. , 2010, Physiological reviews.

[23]  G. Hasenfuss,et al.  CaMKII-Dependent Diastolic SR Ca2+ Leak and Elevated Diastolic Ca2+ Levels in Right Atrial Myocardium of Patients With Atrial Fibrillation , 2010, Circulation research.

[24]  N. Dalton,et al.  Phospholamban Ablation Rescues Sarcoplasmic Reticulum Ca2+ Handling but Exacerbates Cardiac Dysfunction in CaMKII&dgr;C Transgenic Mice , 2010, Circulation research.

[25]  U. Schotten,et al.  Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. , 2009, The Journal of clinical investigation.

[26]  M. Rich,et al.  Epidemiology of atrial fibrillation , 2009, Journal of Interventional Cardiac Electrophysiology.

[27]  S. Nattel,et al.  Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure , 2008, Circulation. Arrhythmia and electrophysiology.

[28]  Chao Zhang,et al.  Suppression of p53-dependent senescence by the JNK signal transduction pathway , 2007, Proceedings of the National Academy of Sciences.

[29]  G. Gross,et al.  Impaired p38 MAPK/HSP27 signaling underlies aging-related failure in opioid-mediated cardioprotection. , 2007, Journal of molecular and cellular cardiology.

[30]  R. Angell,et al.  N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3. , 2007, Bioorganic & medicinal chemistry letters.

[31]  M. Bogoyevitch.  The isoform‐specific functions of the c‐Jun N‐terminal Kinases (JNKs): differences revealed by gene targeting , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[32]  Stephen S. Cha,et al.  Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 2000, and Implications on the Projections for Future Prevalence , 2006, Circulation.

[33]  D. Bers,et al.  Ca2+/Calmodulin–Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphorylation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure , 2005, Circulation research.

[34]  E. Lakatta,et al.  Protection in the aged heart: preventing the heart-break of old age? , 2005, Cardiovascular research.

[35]  M. Karin,et al.  From JNK to Pay Dirt: Jun Kinases, their Biochemistry, Physiology and Clinical Importance , 2005, IUBMB life.

[36]  C. Wilbert,et al.  Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification , 2005, Aging cell.

[37]  Guy Salama,et al.  Calmodulin kinase II inhibition protects against structural heart disease , 2005, Nature Medicine.

[38]  H. Jasper,et al.  JNK signaling confers tolerance to oxidative stress and extends lifespan in Drosophila. , 2003, Developmental cell.

[39]  C. Kuan,et al.  c‐Jun N‐terminal kinases (JNK) antagonize cardiac growth through cross‐talk with calcineurin–NFAT signaling , 2003, The EMBO journal.

[40]  J. Molkentin,et al.  Temporal activation of c‐Jun N‐terminal kinase in adult transgenic heart via cre‐loxP‐mediated DNA recombination , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  S. Nattel,et al.  Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing–Induced Congestive Heart Failure , 2001, Circulation.

[42]  D. Singer,et al.  Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. , 2001, JAMA.

[43]  D M Bers,et al.  Sarcoplasmic reticulum Ca(2+) release causes myocyte depolarization. Underlying mechanism and threshold for triggered action potentials. , 2000, Circulation research.

[44]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[45]  R. Flavell,et al.  Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2. , 1998, Immunity.

[46]  L. Mahadevan,et al.  Anisomycin Selectively Desensitizes Signalling Components Involved in Stress Kinase Activation and fos andjun Induction , 1998, Molecular and Cellular Biology.

[47]  B. Ames,et al.  The free radical theory of aging matures. , 1998, Physiological reviews.

[48]  D. Levy,et al.  Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. , 1994, JAMA.

[49]  V. Fast,et al.  The stress kinase JNK regulates gap junction Cx43 gene expression and promotes atrial fibrillation in the aged heart. , 2018, Journal of molecular and cellular cardiology.

[50]  Xun Ai,et al.  The Stress-Response MAP Kinase Signaling in Cardiac Arrhythmias. , 2016, Reviews of physiology, biochemistry and pharmacology.

[51]  V. Fast,et al.  Ionic mechanism of shock-induced arrhythmias: role of intracellular calcium. , 2012, Heart rhythm.

[52]  E. Wagner,et al.  Antagonistic control of cell fates by JNK and p38-MAPK signaling , 2008, Cell Death and Differentiation.

[53]  M. Karin.  Inflammation-activated protein kinases as targets for drug development. , 2005, Proceedings of the American Thoracic Society.

[54]  Shokei Kim,et al.  Cardiac mitogen-activated protein kinase activities are chronically increased in stroke-prone hypertensive rats. , 1998, Hypertension.