Decreased Ca2+ leak from the Sarcoplasmic Reticulum (RS) protects from early development of pathological cardiac hypertrophy

VÉLEZ-RUEDA OMAR; ROSSETTI NOELIA; MATTIAZZI ALICIA; CELY-ORTIZ ALEJANDRA; DÍAZ ZEGARRA LEANDRO; VALVERDE CARLOS A.; SAPIA LUCIANA; AIELLO ERNESTO A.; DE GIUSTI VERÓNICA

Congreso; REUNIÓN ANUAL DE SOCIEDADES DE BIOCIENCIAS SAIC - SAI - SAFIS; 2020

Abnormal Ca2+ release from the SR, associated with Ca2+-calmodulin kinase II (CaMKII)-dependent phosphorylation of RyR2 at Ser2814, has been linked to cardiac diseases, such as pathological cardiac hypertrophy (PCH) and its progression to heart failure. The increase in SR Ca2+ uptake by phospholamban (PLN) ablation (PLNKO), to restore the decrease in SR Ca2+ load produced by RyR2 phosphorylation, ameliorates SR Ca2+ handling but exacerbates cardiac disease. In the present study, we tested the hypothesis that the abrogation of CaMKII-induced Ca2+ loss by RyR2, induced by CaMKII phosphorylatable site mutation (S2814A), protects the heart from RS Ca2+ overload produced by PLN ablation and delays the development of PCH. We used hearts from 10 weeks old WT, S2814A, PLNKO mice and a crossbreed strain of S2814A and PLNKO generated in our laboratory, named SAKO. Only WT and SAKO strain were subjected to transverse aortic constriction (TAC), a commonly used experimental surgical model for pressure overload-induced PCH, known to be associated with CaMKII overexpression. Cardiac hypertrophy parameters (transthoracic echocardiography) were studied one month after the intervention. SAKO mice were monitored up to 180 days. *p