Effects of Sacubitril/Valsartan on the Expression of CaMKII/Ca_v1.2 in Atrial Fibrillation Stimulation Rabbit Model

Background and Objective. Atrial fibrillation (AF) is linked to high morbidity and death rates throughout the world due to limited therapeutic options and thus presents a major challenge to the developed and developing countries. In this study, we aim to investigate the influence of sacubitril/valsartan (sac/val) treatment on the calmodulin-dependent protein kinase II (CaMKII)/Ca(v)1.2 expression in AF models. Methods. Overall, 18 rabbits were randomly divided into control, pacing (600 beats/min), and pacing+sac/val groups. The rabbits in the pacing+sac/val cohort received oral sac/val (10 mg/kg twice daily) across the 21-day investigation period. After three weeks, the atrial effective refractory period (AERP) and AF induction rate were compared. HL-1 cultures were exposed to fast pacing (24 h) with and without LBQ657 (active sacubitril form)/valsartan. Western blots were used for detecting Ca(v)1.2 and CaMKII expression within atrial muscles of the rabbits and HL-1 cultures of AF model. Results. In comparison to the sham cohort, the AF induction rate was markedly increased together with AERP reduction within pacing cohort. Such changes were markedly rescued through sac/val treatment in pacing+sac/val cohort. The proteomic expression profiles of CaMKII and Ca(v)1.2 showed that the CaMKII expression was markedly upregulated, while Ca(v)1.2 expression was downregulated in the pacing cohort. Importantly, these effects were absent in pacing+sac/val cohort. Conclusion. Results of this study show that sac/val treatment regulates the expression of CaMKII/Ca(v)1.2 and could alter this pathway in atrial rapid electrical stimulation models. Therefore, this investigation could contribute to a novel strategy in AF therapeutics in clinical settings.