CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
PHOSPHORYLATION OF RYANODINE RECEPTORS (RYR2) IS A KEY PLAYER IN THE ISCHEMIA/REPERFUSION-INDUCED INFARCT SIZE AND DECREASE IN CARDIAC FUNCTION
VALVERDE CA; DI CARLO MN; SAID M; WEHRENS XHT; SALAS M; MATTIAZZI A
San Diego - California
Congreso; XXI ISHR World Congress; 2013
We have previously showed that CaMKII-dependent phosphorylations at the sarcoplasmic reticulum are main determinants of the detrimental effects of irreversible cardiac ischemia followed by reperfusion (I/R). The present experiments address the role of CaMKII-mediated phosphorylation of RyR2 on contractility and cardiac infarct size after I/R. Aim: To elucidate whether RyR2 phosphorylation is a key determinant of the progression toward the post-ischemic injury mediated by CaMKII. Experiments were performed in knock-in mice in which an alanine or aspartic acid replaces serine at RyR2-2814 residue (Ser2814A or Ser2814D, respectively), to obtain a constitutively unphosphorylated/phosphorylated Ser2814 site (Ser2814A/Ser2814D). Isolated Langendorff perfused hearts from Ser2814A, Ser2814D mice and their control WT mice,were submitted to global IR (45/120min). Basal parameters of S2814A and Ser2814D did not differ from control hearts. In WT mice, there was a significant increase in the phosphorylation of the CaMKII-dependent Ser2814 residue of RyR2 at the onset of reperfusion, with a peak at 3-5min of reperfusion (210.3±41.9% - 191.1±41.0% of pre-ischemic value).In Ser2814A mice, I/R induced a significant reduction in the infarct size (Ser2814A:16.4±1.6% vs. control:32.1±4.9%) with an improvement in contractility, assessed by left ventricular developed pressure (Ser2814A:7.7±2.0% vs. control:2.1± 0.5% of pre-I), and a lower left ventricular end diastolic pressure during R. In contrast, in Ser2814D mice, both infarct size(30.5± 6.2%) and the contractile recovery(4.6 ± 1.6%) were not different when compared to WT. This somewhat unexpected result may be the consequence of the diminished SR Ca2+ content and the improved fractional Ca2+release described in Ser2814D vs. WT mice (van Oort et al., 2010). Conclusion: Our results suggest that both, CaMKII phosphorylation of RyR2 Ca2+release channels at S2814 and SR Ca2+content are main determinants of the deleterious effects of I/R injury.