CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Na+ overload as a mediator of apoptosis and arrhythmias in heart failure: Role of CaMKII
MARTIN GERARDO VILA PETROFF
Congreso; XX Annual Meeting of the International Society for Heart Research Latin American Section; 2012
Heart failure (HF) is associated with enhanced incidence of arrhythmias and apoptosis, having both these processes been attributed, at least in part to alterations in intracellular Ca2+ handling. Given that Ca2+i regulation is linked to Na+i homeostasis through its effect on Na+/Ca2+ exchanger (NCX) activity and that Na+i levels are increased in the failing heart, it is plausible that elevated Na+i is the initiating step that induces apoptosis and arrhythmias in HF. In addition, the calcium/calmodulin-dependent protein kinase II (CaMKII) is overexpressed in HF and has been shown to mediate apoptosis and arrhythmias. However, whether elevated Na+i leads to an increase in Ca2+i that results in the activation of CaMKII which enables apoptotic and proarrhythmogenic activity has not been evaluated previously. In this study we examined whether elevated Na+i can promote apoptosis and arrhythmias through CaMKII-dependent signaling. For this purpose, Na+i was increased in rat cardiac myocytes by inhibiting the Na+/K+-ATPase (NKA) with ouabain. Na+i elevation enhanced CaMKII activity, induced apoptosis and promoted arrhythmias, effects that were blocked by CaMKII inhibition (KN93; AIP) and enhanced by CaMKII overexpression. Elevated Na+i failed to induce apoptosis and arrhythmias in myocytes isolated from transgenic mice expressing an SR-targeted CaMKII inhibitory peptide (SR-AIP) and both effects were prevented by stabilizing the ryanodine receptor (RyR) with tratacaine and carvedilol. We conclude that elevated Na+i activates CaMKII, which through the phosphorylation of its SR targets promotes apoptosis and arrhythmias. We suggest that CaMKII-dependent phosphorylation of the RyR, resulting in SR Ca2+ leak, could be the common underlying mechanism involved.