Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias

Marco Denegri, José Everardo Avelino-Cruz, Simona Boncompagni, Stefano Andrea De Simone, Alberto Auricchio, Laura Villani, Pompeo Volpe, Feliciano Protasi, Carlo Napolitano, Silvia Giuliana Priori

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

RATIONALE:: Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum. OBJECTIVE:: We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2. METHODS AND RESULTS:: We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias. CONCLUSIONS:: We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application.

Original languageEnglish
Pages (from-to)663-668
Number of pages6
JournalCirculation Research
Volume110
Issue number5
DOIs
Publication statusPublished - Mar 2 2012

Fingerprint

Calsequestrin
Ryanodine Receptor Calcium Release Channel
Viral Genes
Cardiac Arrhythmias
Phenotype
Macromolecular Substances
Mutation
Sudden Cardiac Death
Sarcoplasmic Reticulum
Mutant Proteins
Green Fluorescent Proteins
Heart Arrest
Intraperitoneal Injections
Knockout Mice
Calcium
Genes
Proteins
triadin
Polymorphic catecholergic ventricular tachycardia

Keywords

  • arrhythmias
  • gene therapy
  • genetics
  • sudden death

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias. / Denegri, Marco; Avelino-Cruz, José Everardo; Boncompagni, Simona; De Simone, Stefano Andrea; Auricchio, Alberto; Villani, Laura; Volpe, Pompeo; Protasi, Feliciano; Napolitano, Carlo; Priori, Silvia Giuliana.

In: Circulation Research, Vol. 110, No. 5, 02.03.2012, p. 663-668.

Research output: Contribution to journalArticle

Denegri, Marco ; Avelino-Cruz, José Everardo ; Boncompagni, Simona ; De Simone, Stefano Andrea ; Auricchio, Alberto ; Villani, Laura ; Volpe, Pompeo ; Protasi, Feliciano ; Napolitano, Carlo ; Priori, Silvia Giuliana. / Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias. In: Circulation Research. 2012 ; Vol. 110, No. 5. pp. 663-668.
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AU - Avelino-Cruz, José Everardo

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AU - De Simone, Stefano Andrea

AU - Auricchio, Alberto

AU - Villani, Laura

AU - Volpe, Pompeo

AU - Protasi, Feliciano

AU - Napolitano, Carlo

AU - Priori, Silvia Giuliana

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N2 - RATIONALE:: Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum. OBJECTIVE:: We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2. METHODS AND RESULTS:: We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias. CONCLUSIONS:: We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application.

AB - RATIONALE:: Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum. OBJECTIVE:: We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2. METHODS AND RESULTS:: We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias. CONCLUSIONS:: We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application.

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