Phospholamban ablation rescues reperfusión arrhythmias in hearts with Ca/calmodulin kinase II constitutive phosphorylation of ryanodine receptors, but not myocardium infarction

Abstract

CaMKII-dependent phosphorylation of ryanodine receptors (RyR2) at the onset ofreperfusion has been previously associated with an increase in cardiac damage and Catriggeredarrhythmias (Di Carlo et al., 2014, Said et al., 2011). However, whetherincreasing SR Ca uptake/load would also protect against cardiac damage and Catriggeredarrhythmias or exacerbate them, is unknown and difficult to predict, since thedecrease in SR Ca uptake was associated with a decrease in cytosolic Ca but producedan increase in SR Ca leak. Hypothesis: Increasing SR-Ca uptake by ablation ofphospholamban (PLN) rescues reperfusion arrhythmias but fails to protect againstcardiac damage in a mice model with constitutive CaMKII pseudo-phosphorylation ofRyR2 (S2814D mice), linked to reperfusion arrhythmias and exacerbated infarct size.We developed SDKO mice by crossbreeding PLNKO with S2814D mice. At baseline,S2814D and SDKO mice have structurally normal hearts without arrhythmias.However, after a period of global ischemia (15 minutes) only S2814D mice developedectopic beats (6/7 vs. 1/7 in SDKO mice, P<0.05). In contrast, hearts from SDKOexacerbate infarct size (23.2 ± 0.9 % of risk area, n=5) after a short ischemic period (15min), not only with respect to S2814D hearts (10.8± 2.2%, n=5), but also whencompared to PLNKO hearts (14.3 ± 2.0 %, n=6). Conclusions: Improving SR Ca uptakeby PLN ablation prevents the arrhythmic events triggered by CaMKII-dependentincrease in SR Ca leak but exacerbates cardiac damage. The results underscore thebenefits of increasing SERCA2a activity on reperfusion arrhythmias but reveal adetrimental effect of increasing SR Ca uptake on cardiac injury.