Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity

Author:

Landstrom Andrew P.12ORCID,Yang Qixin13ORCID,Sun Bo1ORCID,Perelli Robin M.2ORCID,Bidzimou Minu-Tshyeto2ORCID,Zhang Zhushan2ORCID,Aguilar-Sanchez Yuriana4ORCID,Alsina Katherina M.4,Cao Shuyi5,Reynolds Julia O.5,Word Tarah A.5,van der Sangen Niels M.R.5,Wells Quinn6ORCID,Kannankeril Prince J.7ORCID,Ludwig Andreas8ORCID,Kim Jeffrey J.9ORCID,Wehrens Xander H.T.5910ORCID

Affiliation:

1. Division of Cardiology, Department of Pediatrics (A.P.L., Q.Y., B.S.), Duke University School of Medicine, Durham, NC

2. Department of Cell Biology, Duke University School of Medicine, Durham, NC (A.P.L., R.M.P., M.-T.B., Z.Z.).

3. Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China (Q.Y.).

4. Integrative Molecular and Biomedical Sciences Program (Y.A.-S., K.M.A.), Baylor College of Medicine, Houston, TX.

5. Department of Molecular Physiology and Biophysics (S.C., J.O.R., T.A.W., N.M.R.v.d.S., X.H.T.W.), Baylor College of Medicine, Houston, TX.

6. Departments of Medicine, Pharmacology, and Biomedical Informatics (Q.W.), Vanderbilt University School of Medicine, Nashville, TN.

7. Center for Pediatric Precision Medicine, Department of Pediatrics (P.J.K.), Vanderbilt University School of Medicine, Nashville, TN.

8. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany (A.L.).

9. Section of Cardiology, Department of Pediatrics (J.J.K., X.H.T.W.), Baylor College of Medicine, Houston, TX.

10. Departments of Neuroscience and Center for Space Medicine and the Cardiovascular Research Institute (X.H.T.W.), Baylor College of Medicine, Houston, TX.

Abstract

Background: Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca 2+ ) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca 2+ clock is critical to understanding nodal arrhythmias. We previously demonstrated a role for Jph2 (junctophilin 2) in regulating Ca 2+ -signaling through inhibition of RyR2 (ryanodine receptor 2) Ca 2+ leak in cardiac myocytes; however, its role in pacemaker function and nodal arrhythmias remains unknown. We sought to determine whether nodal Jph2 expression silencing causes increased sinoatrial and atrioventricular nodal cell automaticity due to aberrant RyR2 Ca 2+ leak. Methods: A tamoxifen-inducible, nodal tissue-specific, knockdown mouse of Jph2 was achieved using a Cre-recombinase-triggered short RNA hairpin directed against Jph2 (Hcn4:shJph2). In vivo cardiac rhythm was monitored by surface ECG, implantable cardiac telemetry, and intracardiac electrophysiology studies. Intracellular Ca 2+ imaging was performed using confocal-based line scans of isolated nodal cells loaded with fluorescent Ca 2+ reporter Cal-520. Whole cell patch clamp was conducted on isolated nodal cells to determine action potential kinetics and sodium-calcium exchanger function. Results: Hcn4:shJph2 mice demonstrated a 40% reduction in nodal Jph2 expression, resting sinus tachycardia, and impaired heart rate response to pharmacologic stress. In vivo intracardiac electrophysiology studies and ex vivo optical mapping demonstrated accelerated junctional rhythm originating from the atrioventricular node. Hcn4:shJph2 nodal cells demonstrated increased and irregular Ca 2+ transient generation with increased Ca 2+ spark frequency and Ca 2+ leak from the sarcoplasmic reticulum. This was associated with increased nodal cell AP firing rate, faster diastolic repolarization rate, and reduced sodium-calcium exchanger activity during repolarized states compared to control. Phenome-wide association studies of the JPH2 locus identified an association with sinoatrial nodal disease and atrioventricular nodal block. Conclusions: Nodal-specific Jph2 knockdown causes increased nodal automaticity through increased Ca 2+ leak from intracellular stores. Dysregulated intracellular Ca 2+ underlies nodal arrhythmogenesis in this mouse model.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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