Keywords
isorhamnetin, atrial fibrillation, CaMKII, MAPK, TRPC, Ca2+-handling
1.INTRODUCTION
Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial morbidity and mortality. The clinical burden of AF has been growing in recent years and is predicted to continue increasing in the future (Williams et al., 2020). Although pulmonary vein isolation is recommended as first-line therapy for patients with symptomatic AF, there are no established preventive therapies (Calkins et al., 2017). Conventional antiarrhythmic drugs that target ion channels in the heart have limitations in terms of their efficacy and side effects, and novel therapeutic targets are needed. Preventive upstream therapy for AF remains a significant, unmet medical need (Nattel et al., 2021).
At least two major pathophysiological mechanisms contribute to AF development: electrical and structural remodeling (Nattel & Harada, 2014). As a process of electrical remodeling, one of the pathogenic mechanisms of AF is the activation of Ca/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates serin 2814 on ryanodine receptor 2 (RyR2), ultimately contributing to increased sarcoplasmic reticulum (SR) Ca2+ leakage (Wang et al., 2018). On the other hand, it has been demonstrated that morphological changes, especially interstitial fibrosis, play an important role in the substrate of AF (He et al., 2011). Atrial fibrosis occurs mainly because of the complex activity of various molecules, such as the mitogen-activated protein kinase (MAPK) family and transforming growth factor beta (TGFβ) (Nattel et al., 2020). These alterations are known as structural remodeling. Transient receptor potential (TRP) channels modulate Ca2+ entry and links the response of cardiac fibroblasts to remodeling stimuli that cause arrhythmias (Rose et al., 2012). Among them, TRP canonical-3 (TRPC3) and TRP canonical-6 (TRPC6) play a major role in cardiac hypertrophy and fibrosis; TRPC3/TRPC6 contributes to the regulation of fibroblast function via the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways, respectively (Harada et al., 2012; Nishida et al., 2007). In summary, modulating electrophysiological functions and improving morphological abnormalities in atrial tissue could be a promising therapeutic strategy for decreasing the initiation of AF.
Isorhamnetin, also known as 3’-methoxyquercetin, is a natural flavonoid commonly found in some plant-derived foods, such as wine and nuts, and is an immediate metabolite of quercetin. We have previously reported that isorhamnetin prevents fibrosis, hypertrophy, and inflammation in an angiotensin (AngII)-infused mouse model and reduces liver fibrosis and hepatic steatosis in non-alcoholic steatohepatitis mouse models by inhibiting the TGFβ pathways (Aonuma et al., 2020; Ganbold et al., 2019). Furthermore, isorhamnetin has been reported to have the ability to regulate vascular Ca2+channels and currents (Saponara et al., 2011; Zhu et al., 2005). These findings suggest that flavonoids can be used as therapeutic targets to ameliorate electrophysiology-related diseases. Moreover, flavonoids have recently been reported to reduce the risk of AF development in high-risk patients in clinical practice; however, detailed reports exploring the mechanisms of this effect are lacking (Bondonno et al., 2020).
This study aimed to investigate the impact of isorhamnetin on AF vulnerability and explore its potential pathways.