Novel preventive effect of isorhamnetin on electrical and structural remodeling in atrial fibrillation. Issue 24 (21st December 2022)

• Record Type: Journal Article
• Authors: Aonuma, Kazuhiro; Xu, DongZhu; Murakoshi, Nobuyuki; Tajiri, Kazuko; Okabe, Yuta; Yuan, Zixun; Li, Siqi; Murakata, Yoshiko; Tominaga, Kenichi; Nogami, Akihiko; Aonuma, Kazutaka; Ieda, Masaki; Isoda, Hiroko
• Is Part Of: Clinical science. Volume 136:Issue 24(2022)
• Page Start: 1831
• Page End: 1849
• Publication Date: 2022-12-21
• Subjects: atrial fibrillation -- Ca2+-handling -- CaMKII -- isorhamnetin -- MAPK -- TRPC; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20220319
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: Isorhamnetin, a natural flavonoid, has strong antioxidant and antifibrotic effects, and a regulatory effect against Ca 2+ -handling. Atrial remodeling due to fibrosis and abnormal intracellular Ca 2+ activities contributes to initiation and persistence of atrial fibrillation (AF). The present study investigated the effect of isorhamnetin on angiotensin II (AngII)-induced AF in mice. 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 group. 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, Ca 2+ imaging with isolated atrial myocytes and HL-1 cells, and action potential duration (APD) measurements using atrial tissue and HL-1 cells were performed. AF-related molecule expression was assessed and histopathological examination was performed. Isorhamnetin decreased AF inducibility compared with the AngII group and restored AngII-induced atrial effective refractory period prolongation. Isorhamnetin eliminated abnormal diastolic intracellular Ca 2+ activities induced by AngII. Isorhamnetin also abrogated AngII-induced APD prolongation and abnormal Ca 2+ 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. The findings of the present study suggest that isorhamnetin prevents AngII-induced AF vulnerability and arrhythmogenic atrial remodeling, highlighting its therapeutic potential as an anti-arrhythmogenic pharmaceutical or dietary supplement.