Progress of circRNA/lncRNA-miRNA-mRNA axis in atrial fibrillation

miRNA-mediated mechanism in AF

miRNA is a type of endogenous small non-coding RNA that can regulate the expression of corresponding target genes and thus participate in most biological processes. miRNA-mediated gene regulation is accomplished through post-transcriptional inhibition of the small RNA seed region, which binds to the three UTRs of the target mRNA. These effects contribute to the formation of a regulatory network of miRNAs on their targets. Many studies have found that miRNAs play an important role in the pathogenesis of AF (Pu et al., 2019). Some miRNAs have been implicated in the progression of AF by participating in atrial fibrosis (Table 1) (Fig. 4). For example, overexpression of miR-27b-3p can regulate the Wnt/β-Catenin signaling pathway by targeting Wnt3a, thereby influencing the activity of the Wnt/β-Catenin pathway to reduce atrial fibrosis and subsequently decrease the incidence and duration of AF (Lv et al., 2019). Another study has shown that miR-205 improves atrial fibrosis by negatively regulating the expression of P4HA3 and interfering with the fibrosis-related JNK pathway (Xiao et al., 2021a). H2S can upregulate the expression of miR-133a in cardiomyocytes, and overexpression of miR-133a can inhibit Ang II-induced cardiomyocyte proliferation and migration, as well as reduce the levels of fibrosis markers and CTGF (Su et al., 2021). Hsa-miR-4443 targets THBS1 and regulates the TGF-β1/α-SMA/collagen pathway, thereby inhibiting HCFB proliferation and collagen synthesis, leading to a reduction in myocardial fibrosis (Xiao et al., 2021b). Some researchers suggest that miR-21 has the potential to predict AF, particularly in combination with NT-proBNP (Sieweke et al., 2020). Quercetin (Que) can promote the expression of miR-135b, resulting in the downregulation of miR-135b target genes TGFBR1 and TGFBR2, which inhibits the activity of the TGF-β/Smads pathway, thereby reducing myocardial fibrosis and collagen deposition (Wang et al., 2021a). Additionally, quercetin has been shown to inhibit the expression of miR-223-3p, increase FOXO3 expression, and activate related autophagy pathways to prevent myocardial fibrosis (Hu et al., 2021). Overexpression of miR-27b has been reported to inhibit the Smad-2/3 signaling pathway by negatively regulating ALK5, thereby attenuating myocardial fibrosis (Wang et al., 2018). Downregulation of miR-10a can target BCL6 and block the TGF-β1/Smads signaling pathway to reduce atrial structural remodeling (Li et al., 2019). Overexpression of miR-29b can improve atrial fibrosis by targeting and regulating the expression of TGFβRΙ, thereby inhibiting the activity of the Smad-2/3 pathway (Han et al., 2022). Downregulation of miR-138-5p can reverse cardiac fibrosis by targeting and inhibiting CYP11B2 (Xie, Fu & Xie, 2018). MiR-29b-3p negatively regulates the PDGF-B signaling pathway to inhibit atrial remodeling (Lv et al., 2021). Upregulation of miR-205-5p negatively regulates EHMT2, which affects the inhibitory role of IGFBP3 in atrial fibrosis (Xiao et al., 2022). MiRNA-148a alleviates cardiomyocyte apoptosis in AF by inhibiting SMOC2 (Zhang, Man & Chen, 2022).

In addition to the inhibitory effects of the aforementioned miRNAs, some miRNAs can also promote myocardial fibrosis (Table 2) (Fig. 5). Research has shown that upregulated miR-146b-5p is positively correlated with the expression of fibrosis markers MMP9, TGFB1, and COL1A1, and it can target and downregulate TIMP4, thereby promoting AF fibrosis (Ye et al., 2021). On one hand, CADM1 has been reported as a potential target of miR-21. Upregulated miR-21 can decrease CADM1 expression, which in turn affects STAT3 expression. STAT3 can induce activation and proliferation of cardiac fibroblasts through TGF-β1, thereby promoting cardiac fibrosis. This suggests that miR-21 is an important signaling molecule in cardiac fibrosis remodeling and AF (Cao, Shi & Ge, 2017). On the other hand, research has shown that overexpression of miR-21 can target WWP-1 to promote TGF-β1/Smad2 signaling pathway and induce proliferation of cardiac fibroblasts (Tao et al., 2018). Similarly, in patients with diabetes and AF, the miR-21 subtype miR-21-3p targets FGFR1, regulating FGFR1/FGF21/PPARγ and further promoting adipose browning, thereby exacerbating myocardial fibrosis (Pan et al., 2021). Soeki et al. (2016) confirmed that plasma levels of miR-328 in AF patients were higher than those in the control group, and the plasma levels of miR-328 in the left atrial appendage (LAA) were positively correlated with the LA voltage zone index, suggesting that miR-328 may be involved in the atrial remodeling process in AF patients. Additionally, miR-455-5p can bind to the target gene SOCS3, activating the STAT3 signaling pathway and accelerating the progression of AF (Li et al., 2021a). MiR-1202 can negatively regulate nNOS expression to activate the TGF-β1/Smad2/3 pathway and promote fibrosis (Xiao et al., 2021c). TGF-β can downregulate the expression of Sema3A through the upregulated miR-181b, thereby inducing EndMT and increasing the degree of atrial fibrosis through the LIMK/p-cofilin signaling pathway (Lai et al., 2022). MiR-23 promotes AF progression by positively regulating TGF-β1 (Yu et al., 2019). IL-6 upregulates miR-210, which targets Foxp3 to inhibit Treg function and promote atrial fibrosis (Chen et al., 2020). Research has shown that overexpression of miR-124-3p can promote fibroblast proliferation by negatively regulating AXIN1 in the WNT/β-catenin signaling pathway (Zhu et al., 2022). Furthermore, overexpression of miR-23b-3p and miR-27b-3p target TGF-β1 and TGFBR3, respectively, and induce atrial fibrosis through the activation of the Smad3 signaling pathway (Yang et al., 2019). A recent study has shown that downregulation of miR-425-5p can promote atrial remodeling by negatively regulating CREB1 (Wei et al., 2022).

In addition to their role in myocardial fibrosis, certain miRNAs can also influence the electrical remodeling of AF. For example, elevated expression levels of miR-155 in AF patients can lead to a decrease in the expression of CACNA1C, resulting in a reduction in L-type Ca2+ density and contributing to AF electrical remodeling (Wang et al., 2021b). Furthermore, downregulation of miR-106b-25 in AF patients has been shown to increase the expression of RyR2 and mediate intracellular Ca2+ elevation, thereby participating in the occurrence and development of AF (Zhu et al., 2019).

Based on these studies, it is evident that miRNAs have broad potential in the diagnosis and treatment of AF.

lncRNA-mediated mechanisms in AF

Long non-coding RNAs (lncRNAs) play crucial roles in various key biological processes (Table 3) (Fig. 6). They are essential for controlling cellular biological processes associated with a wide range of human diseases (Ma, Bajic & Zhang, 2013). For instance, LICPAR has been found to regulate atrial fibrosis through the TGF-β/Smad pathway, providing a potential treatment strategy for AF (Wang et al., 2020). Additionally, NRON(lncRNA) has been shown to alleviate atrial fibrosis by inhibiting M1 macrophage activation in atrial myocytes (Sun et al., 2019). Furthermore, circulating GAS5 (lncRNA)has been identified as a potential biomarker for AF diagnosis and prognosis. The downregulation of GAS5 occurs prior to left atrial enlargement and can be used to predict the progression and recurrence of AF (Shi et al., 2021a). Moreover, the downregulation of TCONS_00016478 may promote atrial energy metabolism remodeling and contribute to the development of AF by inhibiting the PGC1-α/PPARγ signaling pathway (Jiang et al., 2022). These findings highlight the potential of targeting these molecules for the diagnosis and treatment of AF.

CircRNA-mediated mechanism in AF

A group of ncRNAs, known as circRNAs, possess regulatory properties. Their gene expression is more stable, and their molecular structure forms closed loops that are resistant to degradation by RNA exonucleases. Increasing evidence suggests that circRNAs may interact with miRNAs through a sequence-driven sponge effect (Kristensen et al., 2019). This circRNA-miRNA network may play a role in the pathological and physiological processes of cardiovascular diseases. Previous studies have shown that certain circRNAs may be involved in the process of cardiac fibrosis, thereby promoting the occurrence and development of AF (Table 4). For example, Gao et al. (2021) reported that has_circ_0004104 promotes cardiac fibrosis by targeting the MAPK and TGF-β pathways, suggesting its potential as a therapeutic regulator and biomarker for AF. Additionally, mmu_circ_0005019 has been identified to inhibit cardiac fibroblast fibrosis and reverse electrical remodeling of cardiomyocytes, demonstrating its protective role in the development of AF and suggesting its potential as a therapeutic target (Wu et al., 2021). However, the mechanisms of action for these circRNAs in AF have only been partially elucidated. Compared to miRNAs and lncRNAs, circRNAs are relatively understudied, and further extensive clinical and basic experiments are needed to explore the underlying mechanisms between circRNAs and AF.

Interactions among three RNAs

The mediated mechanism of lncRNA, miRNA and mRNA in AF

Upregulated LOC101928304/LRRC2 competitively binds to miR-490-3p, leading to downregulation of miR-490-3p expression (Ke et al., 2022). XIST acts as a ceRNA to inhibit miR-214-3p, resulting in increased expression of Arl2 and attenuated apoptosis of myocardial cells (Yan et al., 2021). NEAT1 negatively regulates miR-320, leading to decreased expression of miR-320, which further inhibits the expression of NPAS2 and suppresses cardiac fibroblast proliferation (Dai et al., 2021b). PVT1 regulates IL-16 expression by targeting miR-145-5p, promoting M1 macrophage polarization and enhancing proliferation of atrial fibroblasts (Cao et al., 2021).

Furthermore, several lncRNAs are involved in AF electrical remodeling. For example, miRNA-328 negatively regulates TCONS_00075467 and subsequently modulates the downstream protein-coding gene CACNA1C to counteract the effects on electrical remodeling (Li et al., 2017). Downregulated FAM201A regulates RAC3 expression by targeting miR-33a-3p, promoting autophagy and reducing L-type calcium channels, thereby increasing the incidence of AF (Chen et al., 2022). TCONS-00106987 sponge miR-26 and further regulates KCNJ2, promoting atrial electrical remodeling during AF. These studies reveal a pathogenic lncRNA-miRNA regulatory network associated with AF, providing potential therapeutic targets for AF treatment (Du et al., 2020).