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

MAZZOCCHI G; DI CARLO MN; VALVERDE CA; KRANIAS EG; WEHRENS XH; MATTIAZZI A

Ciudad Autónoma de Buenos Aires

Congreso; XXII ISHR WORLD CONGRESS 2016; 2016

International Society for Heart Research

CaMKII-dependent phosphorylation of ryanodine receptors (RyR2) at theonset of reperfusion has been previously associated with an increase in cardiacdamage and Ca-triggered arrhythmias (Di Carlo et al., 2014,Said et al., 2011). However, whether increasing SR Ca uptake/load would also protect against cardiacdamage and Ca-triggeredarrhythmias 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 of phospholamban (PLN) rescuesreperfusion arrhythmias but fails to protect against cardiac damage in a micemodel with constitutive CaMKII pseudo-phosphorylation of RyR2 (S2814D mice),linked to reperfusion arrhythmias and exacerbated infarct size. We developedSDKO mice by crossbreeding PLNKO with S2814D mice. At baseline, S2814D and SDKO mice have structurally normalhearts without arrhythmias. However, after a period of global ischemia (15minutes) only S2814D mice developed ectopicbeats (3/5 vs. 0/3 in SDKO mice,P<0.05) and ventricular tachycardia, (1/5 vs 0/3 in SDKO, P<0.05). In contrast, hearts from SDKO exacerbateinfarct size (23.2 ± 0.9 % of risk area, n=5) after a short ischemic period (15min), not only with respect to S2814D hearts (9.2± 3.4%, n=3), but also whencompared to PLNKO hearts (14.3 ± 2.0 %, n=6), with a similar degree ofenergetic cost than SDKO hearts. Conclusions: Improving SR Ca uptake byPLN ablation prevents the arrhythmic events triggered by CaMKII-dependent increasein 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.