Conflict of interest
The authors have declared that no conflict of interest exists.
Abstrac t
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.