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》

LncRNA MIAT/miR-133a-3p axis regulates atrial fibrillation and atrial fibrillation-induced myocardial fibrosis.

Yao L ，Zhou B ，You L ，Hu H ，Xie R ... -  《-》

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 ... -  《-》

Endothelial progenitor cells-secreted extracellular vesicles containing microRNA-93-5p confer protection against sepsis-induced acute kidney injury via the KDM6B/H3K27me3/TNF-α axis.

The pivotal pathogenetic role of microRNAs (miRs) in sepsis-induced acute kidney injury (AKI) has been demonstrated in mounting evidence. The functions of the target cells are regulated through the release of cells-encapsulated extracellular vesicles (Evs) into the extracellular space. The present study aims to elucidate the clinical significance as well as biological function of the endothelial progenitor cell (EPC)-derived Evs containing miR-93-5p in sepsis-induced AKI. We first established a cellular sepsis-induced AKI mouse model by treatment with lipopolysaccharide (LPS), and tested ectopic expression and depletion experiments in the model. Evs derived from miR-93-5p inhibitor-transfected EPCs (Evs/miR-93-5p inhibitor) were isolated, and co-cultured with HK2 cells to explore the effects of EPC-derived Evs overexpressing miR-93-5p on LPS-induced HK2 cell injury. The interaction between miR-93-5p and lysine (K)-specific demethylase 6B (KDM6B) was identified using dual-luciferase reporter assay, and ChIP was used to validate the relationship between KDM6B and tumor necrosis factor-α (TNF-α). Mice were made septic by cecal ligation and puncture (CLP), and then injected with Ev/miR-93-5p inhibitor to explore its functions in vivo. The results found that miR-93-5p and histone H3 Lys27 trimethylation (H3K27me3) were downregulated while KDM6B was upregulated in LPS-treated HK2 cells. EPC-derived Evs alleviated LPS-induced HK2 cell injury, while Ev/miR-93-5p inhibitor potentiated the cell injury in vitro. miR-93-5p was found to directly target KDM6B. Silencing KDM6B induced H3K27me3, inhibiting the activation of TNF-α, thereby weakening LPS-induced HK2 cell injury. EPC-derived Evs containing miR-93-5p attenuated multiple organ injury, vascular leakage, inflammation, and apoptosis in septic mice. In conclusion, the present study demonstrated that endothelial protection from EPC-derived Evs carrying miR-93-5p in sepsis-induced AKI, which was mediated by regulation KDM6BH/3K27me3/TNF-α axis.

He Z ，Wang H ，Yue L 《-》

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 ... -  《-》