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


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.
Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
Marco
M
Denegri
José Everardo
JE
Avelino-Cruz
Simona
S
Boncompagni
Stefano Andrea
SA
De Simone
Alberto
A
Auricchio
Laura
L
Villani
Pompeo
P
Volpe
Feliciano
F
Protasi
Carlo
C
Napolitano
Silvia Giuliana
SG
Priori
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D018014:Gene Transfer Techniques; D006352:Heart Ventricles / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D002352:Carrier Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; C070048:triadin; C498841:Asph protein, mouse; D006899:Mixed Function Oxygenases