Journal of Bioenergetics and Biomembranes最新文献

To investigate the role and molecular mechanisms of the RNA-binding protein MATR3 in myocardial fibrosis of atrial fibrillation (AF). Expression of MATR3 and MSI2 in AF patients was analyzed using GEO datasets (GSE79768, GSE14975, GSE31821). Human atrial fibroblasts (HAFs) induced by Angiotensin II (Ang-II) were used as an in vitro cellular model of myocardial fibrosis. Expression and interactions of MATR3, METTL3, and MSI2 were validated by qRT-PCR and Western blot. The binding between MATR3 and METTL3 was confirmed by co-immunoprecipitation (Co-IP). The m⁶A modification level of MSI2 mRNA was detected by methylated RNA immunoprecipitation (MeRIP-qPCR). Cell proliferation, migration, and fibrotic phenotypes were evaluated by CCK-8, EdU, scratch, and Transwell assays, as well as detection of fibrosis markers. An Ang-II-induced mouse model of atrial fibrosis was constructed, and the in vivo effects of MATR3 were verified by HE staining, Masson's trichrome staining, and molecular detection. Analysis of GEO datasets showed that both MATR3 and MSI2 were highly expressed in AF patients. Ang-II treatment significantly upregulated the expression of MATR3 in HAFs, while knockdown of MATR3 inhibited Ang-II-induced proliferation, migration, and pro-fibrotic phenotypic changes in HAFs (reducing the expression of α-SMA, collagen I/III). Mechanistically, MATR3 interacted endogenously with METTL3 and stabilized the METTL3 protein by inhibiting proteasomal degradation. METTL3 mediated the m⁶A modification of MSI2 mRNA, enhancing its stability and promoting its expression. MSI2 exerted a pro-fibrotic effect by activating the Wnt/β-Catenin pathway. In vivo experiments confirmed that silencing MATR3 downregulated the expression of METTL3 and MSI2, inhibited the activation of the Wnt pathway, and alleviated Ang-II-induced atrial fibrosis in mice. MATR3 promotes myocardial fibrosis and exacerbates AF by regulating METTL3-mediated m⁶A modification of MSI2 mRNA to activate the Wnt/β-Catenin pathway. Targeting MATR3 may represent a potential therapeutic strategy for AF.

Background: Acute myocardial infarction (AMI) is a major cardiovascular disease. Exosomes from mesenchymal stem cells (MSCs) are known to ameliorate myocardial ischemia-reperfusion (I/R) injury, and aberrant expression of UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is linked to cardiovascular pathologies. However, it remains unclear whether MSC-derived exosomes mediate myocardial I/R injury by regulating UBIAD1.

Methods: MSCs were identified by flow cytometry and differentiation assays (Alizarin Red and Oil Red O). Exosomes were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), western blot, and immunofluorescence. Differentially expressed genes were analyzed using bioinformatics analysis. An in vitro H/R damage model was established. Protein expression was examined by western blot. For function, the cell viability, lactate dehydrogenase (LDH), malonaldehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels were detected using corresponding assay kits. Cell apoptosis was examined using flow cytometry. Cross-analysis of the transcription factors predicting UBIAD1 in hTFtarget with highly expressed genes in GSE202991 was analyzed using a Venn diagram. Besides, the interaction between ZEB1 and UBIAD1 was predicted and verified via JASPAR database, chromatin immunoprecipitation assay (ChIP) and dual-luciferase reporter assays.

Results: Up-regulated UBIAD1 mitigated H/R-induced injury in AC16 cells. Conversely, silencing UBIAD1 abrogated MSC-Exo-induced action of mitigation on H/R-induced AC16 cell injury. ZEB1 could bond to UBIAD1. Moreover, exosomes derived from sh-ZEB1-transfected MSCs reduced H/R-induced apoptosis and oxidative stress in cardiomyocytes. Importantly, exosomal ZEB1 alleviated H/R‑induced apoptosis, oxidative stress, and endoplasmic reticulum stress (ERS) through increasing UBIAD1.

Conclusion: MSC-derived exosomal ZEB1 remits H/R-stimulated cardiomyocyte apoptosis, oxidative stress, and ERS via regulating UBIAD1.