Calmodulin kinase II inhibition prevents arrhythmias in RyR2(R4496C+/-) mice with catecholaminergic polymorphic ventricular tachycardia.

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by life-threatening arrhythmias elicited by adrenergic activation. CPVT is caused by mutations in the cardiac ryanodine receptor gene (RyR2). In vitro studies demonstrated that RyR2 mutations respond to sympathetic activation with an abnormal diastolic Ca(2+) leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2(R4496C+/-) knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) counteracts the effects of adrenergic stimulation resulting in an antiarrhythmic activity. CaMKII inhibition with KN-93 completely prevented catecholamine-induced sustained ventricular tachyarrhythmia in RyR2(R4496C+/-) mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2(R4496C+/-) mice, CaMKII inhibition with an autocamtide-2 related inhibitory peptide or with KN-93 blunted triggered activity and transient inward currents induced by isoproterenol. Isoproterenol also enhanced the activity of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), increased spontaneous Ca(2+) release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca(2+) content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2(R4496C+/-) knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca(2+) leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT.

• Authors: Nian Liu, Yanfei Ruan, Marco Denegri, Tiziana Bachetti, Yang Li, Barbara Colombi, Carlo Napolitano, William A Coetzee, Silvia G Priori
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 50 Issue 1 Pg. 214-22 (Jan 2011) ISSN: 1095-8584 [Electronic] England
• PMID: 20937285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Benzylamines
• KN 92
• Ryanodine Receptor Calcium Release Channel
• Sulfonamides
• KN 93
• Caffeine
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Calcium
• Epinephrine

Topics

• Animals
• Arrhythmias, Cardiac (metabolism, prevention & control)
• Benzylamines (pharmacology)
• Blotting, Western
• Caffeine (pharmacology)
• Calcium (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors)
• Electrophysiology
• Epinephrine (pharmacology)
• Mice
• Myocytes, Cardiac (drug effects, metabolism)
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)
• Sulfonamides (pharmacology)
• Tachycardia (metabolism)