Calmodulin kinase II inhibition prevents arrhythmias in RyR2R4496C+/- mice with catecholaminergic polymorphic ventricular tachycardia

Nian Liu, Yanfei Ruan, Marco Denegri, Tiziana Bachetti, Yang Li, Barbara Colombi, Carlo Napolitano, William A. Coetzee, Silvia G. Priori

Research output: Contribution to journalArticle

68 Citations (Scopus)

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 Ca2+ leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2R4496C+/- knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca2+/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 RyR2R4496C+/- mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2R4496C+/- 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 Ca2+-ATPase (SERCA), increased spontaneous Ca2+ release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca2+ content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2R4496C+/- knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca2+ leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT.

Original languageEnglish
Pages (from-to)214-222
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume50
Issue number1
DOIs
Publication statusPublished - Jan 2011

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Cardiac Arrhythmias
Ryanodine Receptor Calcium Release Channel
Adrenergic Agents
Sarcoplasmic Reticulum
Isoproterenol
Catecholamines
Mutation
Calcium-Transporting ATPases
Tachycardia
Muscle Cells
Polymorphic catecholergic ventricular tachycardia
Peptides
Genes

Keywords

  • Calcium handling
  • Catecholamine
  • Genetics
  • Therapy
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

@article{c75e1ff37c8b4282afa0a1635c4b5cb2,
title = "Calmodulin kinase II inhibition prevents arrhythmias in RyR2R4496C+/- 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 Ca2+ leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2R4496C+/- knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca2+/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 RyR2R4496C+/- mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2R4496C+/- 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 Ca2+-ATPase (SERCA), increased spontaneous Ca2+ release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca2+ content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2R4496C+/- knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca2+ leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT.",
keywords = "Calcium handling, Catecholamine, Genetics, Therapy, Ventricular tachycardia",
author = "Nian Liu and Yanfei Ruan and Marco Denegri and Tiziana Bachetti and Yang Li and Barbara Colombi and Carlo Napolitano and Coetzee, {William A.} and Priori, {Silvia G.}",
year = "2011",
month = "1",
doi = "10.1016/j.yjmcc.2010.10.001",
language = "English",
volume = "50",
pages = "214--222",
journal = "Journal of Molecular and Cellular Cardiology",
issn = "0022-2828",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Calmodulin kinase II inhibition prevents arrhythmias in RyR2R4496C+/- mice with catecholaminergic polymorphic ventricular tachycardia

AU - Liu, Nian

AU - Ruan, Yanfei

AU - Denegri, Marco

AU - Bachetti, Tiziana

AU - Li, Yang

AU - Colombi, Barbara

AU - Napolitano, Carlo

AU - Coetzee, William A.

AU - Priori, Silvia G.

PY - 2011/1

Y1 - 2011/1

N2 - 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 Ca2+ leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2R4496C+/- knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca2+/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 RyR2R4496C+/- mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2R4496C+/- 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 Ca2+-ATPase (SERCA), increased spontaneous Ca2+ release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca2+ content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2R4496C+/- knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca2+ leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT.

AB - 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 Ca2+ leak from the sarcoplasmic reticulum; however the pathways that mediate the response to adrenergic stimulation have not been defined. In our RyR2R4496C+/- knock-in mouse model of CPVT we tested the hypothesis that inhibition of Ca2+/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 RyR2R4496C+/- mice, while the inactive congener KN-92 had no effect. In ventricular myocytes isolated from the hearts of RyR2R4496C+/- 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 Ca2+-ATPase (SERCA), increased spontaneous Ca2+ release and spark frequency. CaMKII inhibition blunted each of these parameters without having an effect on the SR Ca2+ content. Our data therefore indicate that CaMKII inhibition is an effective intervention to prevent arrhythmogenesis (both in vivo and in vitro) in the RyR2R4496C+/- knock-in mouse model of CPVT. Mechanistically, CAMKII inhibition acts on several elements of the EC coupling cascade, including an attenuation of SR Ca2+ leak and blunting catecholamine-mediated SERCA activation. CaMKII inhibition may therefore represent a novel therapeutic target for patients with CPVT.

KW - Calcium handling

KW - Catecholamine

KW - Genetics

KW - Therapy

KW - Ventricular tachycardia

UR - http://www.scopus.com/inward/record.url?scp=78650819612&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78650819612&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2010.10.001

DO - 10.1016/j.yjmcc.2010.10.001

M3 - Article

C2 - 20937285

AN - SCOPUS:78650819612

VL - 50

SP - 214

EP - 222

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

SN - 0022-2828

IS - 1

ER -