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.