TY - JOUR
T1 - Relevance of calmodulin/CaMKII activation for arrhythmogenesis in the AV block dog
AU - Bourgonje, Vincent J. A.
AU - Schoenmakers, Marieke
AU - Beekman, Jet D. M.
AU - van der Nagel, Roel
AU - Houtman, Marien J. C.
AU - Miedema, Lars F.
AU - Antoons, Gudrun
AU - Sipido, Karin
AU - de Windt, Leon J.
AU - van Veen, Toon A. B.
AU - Vos, Marc A.
PY - 2012/11
Y1 - 2012/11
N2 - BACKGROUND The calcium-dependent signaling molecules calcineurin and calcium/calmodulin-dependent protein kinase II (CaMKII) both have been linked to decompensated hypertrophy and arrhythmias. CaMKII is also believed to be involved in acute modulation of ion channels. OBJECTIVE The purpose of this study was to determine the role of calcineurin and CaMKII in a dog model of compensated hypertrophy and a long QT phenotype. METHODS AV block was created in dogs to induce ventricular remodeling, including enhanced susceptibility to dofetilide-induced torsades de pointes arrhythmias. Dogs were treated with cyclosporin A for 3 weeks, which reduced calcineurin activity, as determined by mRNA expression levels of regulator of calcineurin 1 exon 4, but which was unable to prevent structural, contractile, or electrical remodeling and arrhythmias. Biopsies were taken before and at 2 or 9 weeks after AV block. Western blots were performed against phosphorylated and total CaMKII, phospholamban, Akt, and histone deacetylase 4 (HDAC4). RESULTS Chronic AV block showed an increase in Akt, CaMKII and phospholamban phosphorylation levels, but HDAC4 phosphorylation remained unaltered. Dofetilide induced torsades de pointes in vivo and early afterdepolarizations in cardiomyocytes, and increased [Ca2+](i) and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this. CONCLUSION The calcineurin pathway seems not to be involved in long-term cardiac remodeling of the chronic AV block dog. Although CaMKII is chronically activated, this does not translate to HDAC4 phosphorylation. However, acute CaMKII overactivation is able to initiate arrhythmias based on triggered activity.
AB - BACKGROUND The calcium-dependent signaling molecules calcineurin and calcium/calmodulin-dependent protein kinase II (CaMKII) both have been linked to decompensated hypertrophy and arrhythmias. CaMKII is also believed to be involved in acute modulation of ion channels. OBJECTIVE The purpose of this study was to determine the role of calcineurin and CaMKII in a dog model of compensated hypertrophy and a long QT phenotype. METHODS AV block was created in dogs to induce ventricular remodeling, including enhanced susceptibility to dofetilide-induced torsades de pointes arrhythmias. Dogs were treated with cyclosporin A for 3 weeks, which reduced calcineurin activity, as determined by mRNA expression levels of regulator of calcineurin 1 exon 4, but which was unable to prevent structural, contractile, or electrical remodeling and arrhythmias. Biopsies were taken before and at 2 or 9 weeks after AV block. Western blots were performed against phosphorylated and total CaMKII, phospholamban, Akt, and histone deacetylase 4 (HDAC4). RESULTS Chronic AV block showed an increase in Akt, CaMKII and phospholamban phosphorylation levels, but HDAC4 phosphorylation remained unaltered. Dofetilide induced torsades de pointes in vivo and early afterdepolarizations in cardiomyocytes, and increased [Ca2+](i) and CaMKII autophosphorylation. Both W-7 and KN-93 treatment counteracted this. CONCLUSION The calcineurin pathway seems not to be involved in long-term cardiac remodeling of the chronic AV block dog. Although CaMKII is chronically activated, this does not translate to HDAC4 phosphorylation. However, acute CaMKII overactivation is able to initiate arrhythmias based on triggered activity.
KW - Arrhythmias
KW - Calcineurin
KW - CaMKII
KW - Chronic AV block dog
KW - Ventricular remodeling
U2 - 10.1016/j.hrthm.2012.07.023
DO - 10.1016/j.hrthm.2012.07.023
M3 - Article
C2 - 22846339
SN - 1547-5271
VL - 9
SP - 1875-1883.e2
JO - Heart Rhythm
JF - Heart Rhythm
IS - 11
ER -