Impact of isorhamnetin for suppression of electrical and structural remodeling via CaMKII-RyR2 and TRPC-mediated MAPK pathways in atrial fibrillation

Background and Purpose: Isorhamnetin, a natural flavonoid, has strong antioxidant and anti-fibrotic effects, and a regulatory effect against Ca2+-handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca2+ activities contributes to initiation and persistence of atrial fibrillation (AF). This study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. Experimental Approach: Wild-type male mice (C57BL/6J, 8 weeks old) were assigned to three groups: (1) control group, (2) AngII-treated group, and (3) AngII-and isorhamnetin-treated groups. AngII (1000 ng/kg/min) and isorhamnetin (5 mg/kg) were administered continuously via an implantable osmotic pump for two weeks and intraperitoneally one week before initiating AngII administration, respectively. AF induction and electrophysiological studies, Ca2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Key Results: Isorhamnetin decreased AF inducibility compared to the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca2+ loading in HL-1 cells. Furthermore, isorhamnetin strongly attenuated AngII-induced left atrial enlargement and atrial fibrosis. AngII-induced elevated expression of AF-associated molecules, such as ox-CaMKII, p-RyR2, p-JNK, p-ERK, and TRPC3/6, was improved by isorhamnetin treatment. Conclusion and Implications: The findings of this study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling via modulating CaMKII-RyR2 and TRPC-mediated MAPK pathways, highlighting its potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.