CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Role of Calcium sequestration by the sarcoplasmic reticulum in CaMKII -induced arrhythmias and cardiac damage
VALVERDE, CARLOS, A; MAZZOCCHI, GABRIELA; MATTIAZZI ALICIA; DI CARLO, MARIANO N
Workshop; STRATEGIC WORKSHOP PROGRAM; 2016
Sociedad Brasileira de Fisiologia
Background: Mice with constitutive phosphorylation of RyR2 at Ser2814 (S2814D mice) exhibit a higher open probability of RyR2 and sarcoplasmic reticulum (SR) Ca2+ leak in diastole. This anomaly increases the propensity to arrhythmias and reperfusion damage (infarct). Although abnormal Ca2+ release from the SR has been linked to arrhythmogenesis and ischemia/reperfusion-induced cell death, the role played by SR Ca2+ uptake remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to rescue from reperfusion arrhythmias and infarction. Methods and Results: To test this hypothesis, we generated PLN-deficient S2814D knock-in mice by crossing the two colonies, i.e. PLNKO and S2814D mice. This new colony was named SDKO mice. Mice were submitted to 15min ischemia/30min reperfusion (I/R) to assess both cardiac damage and reperfusion arrhythmias. At baseline, S2814D and SDKO mice had structurally normal hearts without arrhythmias. PLN ablation (SDKO mice), was able to prevent the arrhythmias evoked by I/R in S2814D mice. In contrast, ablation of PLN was unable to prevent cardiac damage (infarct size and KDH release), but further increase both of them. The mechanisms of these apparent contradictory results were also studied: Ablation of PLN converted Ca2+ waves, which are the substrate of ventricular arrhythmias, into non propagated events (Ca2+ mini-waves), which are unable to generate arrhythmias. Instead, PLN ablation and the consequent increase in Ca2+ sequestration by the SR, was not capable to avoid the reperfusion-induced increase of Ca2+ in the mitochondria in SDKO mice, and therefore the infarct and LDH release. Conclusions: Our results demonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced-SR Ca2+ leak and underscore the benefits of increasing SERCA2a activity on SR Ca2+ triggered arrhythmias. However, it cannot preclude the cardiac damage produced by CaMKII-dependent phosphorylation of RyR2.