miR-425-5p is negatively associated with atrial fibrosis and promotes atrial remodeling by targeting CREB1 in atrial fibrillation.

Progression of atrial fibrosis is vital for atrial remodeling in atrial fibrillation (AF). The main objective of the present study was to explore the association between miR-425-5p and atrial fibrosis as well as the resultant impact on atrial remodeling in AF. Firstly, miRNAs sequencing and quantitative real-time polymerase chain reaction was used to screen and verify the miRNAs expression level in plasma and atrial tissue in AF patients. The left atrial fibrosis was evaluated with the left atrial low voltage area by using left atrial voltage matrix mapping. Cell counting kit-8 was used to detect fibroblasts proliferation. The AF mouse model was established using acetylcholine-CaCl2 injection for 7 days. Target gene prediction software, luciferase assay, and western blotting were employed to confirm the direct targets of miR-425-5p. Firstly, we demonstrated that miR-425-5p was downregulated in plasma and atrial tissue among the patients who suffered from AF. We then confirmed that the plasma's miR-425-5p level was negatively correlated with left atrial fibrosis in persistent AF, and catheter ablation could restore the decreased plasma miR-425-5p. Besides, receiver operating characteristic curve analysis revealed the miR-425-5p not only could differentiate AF from healthy control wit area under the curve (AUC) 0.921, but also discriminated persistent AF from paroxysmal AF with AUC 0.888. Furthermore, downregulation of miR-425-5p could promote atrial remodeling, and overexpression of miR-425-p could improve atrial remodeling and decrease susceptibility to atrial fibrillation. Finally, CREB1 was verified to be a direct target for miR-425-5p. Our findings suggested that miR-425-5p could serve as novel atrial fibrosis biomarker and contributed to atrial remodeling in AF.

Wei F ，Ren W ，Zhang X ，Wu P ，Fan J ... -  《-》

MCPIP1 promotes atrial remodeling by exacerbating miR-26a-5p/FRAT/Wnt axis-mediated atrial fibrosis in a rat model susceptible to atrial fibrillation.

Li K ，Sun H ，Bo Y ，Zhang W ，Huang W ，Zhao Y ，Yang H ，Guo Y ，Zhou X ，Lu Y ，Zhang L ，Tang B ... -  《-》

Integrated analysis of microRNA and mRNA expression profiles in the left atrium of patients with nonvalvular paroxysmal atrial fibrillation: Role of miR-146b-5p in atrial fibrosis.

Studies have reported that the integrated analysis of microRNA (miRNA)-messenger RNA (mRNA) expression is valuable in exploring gene regulation systemically. The objectives of this study were to identify miRNAs and genes involved in atrial fibrillation and to explore the mechanisms underlying atrial fibrosis. We used microarrays to compare the differences in both miRNA and mRNA expression profiles in the left atrial appendage of patients with nonvalvular paroxysmal atrial fibrillation and healthy controls. Furthermore, the quantitative real-time polymerase chain reaction was used to confirm the reliability of the microarray data, prediction of the adopted databases, and Ingenuity Pathway Analysis of miRNA-mRNA expression in order to identify the miRNA target genes, examine the functions and pathways in which the target genes are involved, and construct an miRNA-target gene regulatory network. We further investigated the roles of miRNA-146b-5p in the mechanisms of atrial fibrosis. We identified 10 differentially expressed miRNAs and 624 differentially expressed mRNAs, among which only 1 miRNA-target gene pair miR-146b-5p and tissue inhibitor of metalloproteinase 4 (TIMP-4) were constructed. The validated results revealed that miR-146b-5p, matrix metallopeptidase 9, and collagen content were upregulated whereas TIMP-4 was downregulated in patients with atrial fibrillation. After the transfection of miR-146b-5p into cardiac fibroblasts, TIMP-4 expression was markedly reduced and collagen content was increased. Moreover, luciferase results confirmed that TIMP-4 was a target of miR-146b-5p. The identified miRNA and mRNA may represent a potentially novel molecular regulatory network, which may provide a better understanding of the molecular basis of remodeling in atrial fibrillation. miR-146b-5p probably acts as an intracellular mediator in the maladaptive remodeling in atrial fibrosis in atrial fibrillation.

Wang J ，Wang Y ，Han J ，Li Y ，Xie C ，Xie L ，Shi J ，Zhang J ，Yang B ，Chen D ，Meng X ... -  《-》

Serum extracellular vesicles containing MIAT induces atrial fibrosis, inflammation and oxidative stress to promote atrial remodeling and atrial fibrillation via blockade of miR-485-5p-mediated CXCL10 inhibition.

Atrial fibrillation (AF), a supraventricular arrhythmia that impairs cardiac function, is a main source of morbidity and mortality. Serum-derived extracellular vesicles (EVs) have been identified to carry potential biomarker or target for the diagnosis and treatment of AF. We intended to dissect out the role of lncRNA MIAT enriched in serum-derived EVs in AF. MIAT expression was quantified in EVs isolated from serum samples of AF patients. Mouse and cell models of AF were developed after angiotensin II (Ang II) induction. Relationship between MIAT, miR-485-5p, and CXCL10 was identified. Ectopic expression and depletion assays were implemented in Ang II-treated mice or HL-1 cells, or those co-cultured with serum-derived EVs to explore the roles of EV-carried MIAT. MIAT was upregulated in EVs from serum samples of AF patients. Further analysis indicated that MIAT enriched in serum-derived EVs promoted atrial fibrosis, inflammation and oxidative stress, and aggravated the atrial remodeling and resultant AF. Mechanistically, MIAT bound to miR-485-5p and weakened its inhibitory role on the target CXCL10, which was responsible for the role of serum-derived EV containing MIAT in cellular fibrosis, oxidative stress and inflammation, and atrial remodeling in vivo. In conclusion, serum-derived EV containing MIAT facilitates atrial remodeling and exacerbates the AF by abolishing the miR-485-5p-mediated CXCL10 inhibition. This finding aids in the deeper understanding about the pathophysiology of AF.

Chen Y ，Chen X ，Li H ，Li Y ，Cheng D ，Tang Y ，Sang H ... -  《Clinical and Translational Medicine》

Construction and integrated analysis of the ceRNA network hsa_circ_0000672/miR-516a-5p/TRAF6 and its potential function in atrial fibrillation.

Atrial fibrosis is a crucial contributor to initiation and perpetuation of atrial fibrillation (AF). This study aimed to identify a circRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory network related to atrial fibrosis in AF, especially to validate hsa_circ_0000672/hsa_miR-516a-5p/TRAF6 ceRNA axis in AF preliminarily. The circRNA-miRNA-mRNA ceRNA network associated with AF fibrosis was constructed using bioinformatic tools and literature reviews. Left atrium (LA) low voltage was used to represent LA fibrosis by using LA voltage matrix mapping. Ten controls with sinus rhythm (SR), and 20 patients with persistent AF including 12 patients with LA low voltage and 8 patients with LA normal voltage were enrolled in this study. The ceRNA regulatory network associated with atrial fibrosis was successfully constructed, which included up-regulated hsa_circ_0000672 and hsa_circ_0003916, down-regulated miR-516a-5p and five up-regulated hub genes (KRAS, SMAD2, TRAF6, MAPK11 and SMURF1). In addition, according to the results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, these hub genes were clustered in TGF-beta and MAPK signaling pathway. In the patients with persistent AF, hsa_circ_0000672 expression in peripheral blood monocytes was significantly higher than those in controls with SR by quantitative real-time polymerase chain reaction (p-value < 0.001). Furthermore, hsa_circ_0000672 expression was higher in peripheral blood monocytes of persistent AF patients with LA low voltage than those with LA normal voltage (p-value = 0.002). The dual-luciferase activity assay confirmed that hsa_circ_0000672 exerted biological functions as a sponge of miR-516a-5p to regulate expression of its target gene TRAF6. Hsa_circ_0000672 expression in peripheral blood monocytes may be associated with atrial fibrosis. The hsa_circ_0000672 may be involved in atrial fibrosis by indirectly regulating TRAF6 as a ceRNA by sponging miR-516a-5p.

Liu X ，Wu M ，He Y ，Gui C ，Wen W ，Jiang Z ，Zhong G ... -  《Scientific Reports》