Fibroblast-specific knockout of METTL1 attenuates myocardial infarction-induced cardiac fibrosis.

Cardiac fibrosis, a common pathology in inherited and acquired heart diseases, necessitates the identification of diagnostic and therapeutic targets. Methyltransferase Like 1 (METTL1), an enzyme responsible for RNA modification by methylating guanosine to form m7G, is an emerging area of research in understanding cellular processes and disease pathogenesis. Dysregulation of m7G modification has been implicated in various diseases. However, the role of METTL1 in cardiac fibrosis remains unclear. This study aimed to investigate the role of METTL1 in myocardial infarction-induced heart failure and cardiac fibrosis. Our findings demonstrate that elevated METTL1-mediated RNA m7G methylation is observed in cardiac fibrosis tissues and TGF-ß1-induced cardiac fibroblast proliferation and myofibroblast transformation. Furthermore, fibroblast-specific knockout of METTL1 attenuated myocardial infarction-induced heart failure and cardiac fibrosis. Additionally, METTL1 knockout decreased m7G methylated fibrotic genes and impaired their translation efficiency. These results suggest a novel pro-fibrosis role of METTL1-mediated RNA m7G methylation, highlighting its potential as a therapeutic target in cardiac fibrosis.

Long noncoding RNA CASC2 protect ROS-induced oxidative stress in myocardial infarction by miR-18a/SIRT2.

We aimed to investigate the function and its possible mechanisms of long noncoding RNA (lncRNA) in acute myocardial infarction (AMI) model. Patients with AMI and normal volunteers were selected from our hospital. Sprague-Dawley rats were induced into in vivo model of AMI. H9c2 cells were treated with H2 O2 to generate injury model. A significantly lower serum gene expression of lncRNA CASC2 was detected. In rat models of AMI, lncRNA CASC2 gene expressions in heart tissue of mice with AMI were decreased. In in vitro model, downregulation of lncRNA CASC2 increased reactive oxygen species (ROS)-induced oxidative stress; lncRNA CASC2 induced NADPH oxidase (NOX-2) expression and suppressed miR-18a expression; MiR-18a promoted ROS-induced oxidative stress; downregulation of miR-18a decreased ROS-induced oxidative stress. The inhibition of miR-18a reversed the effects of CASC2 downregulation on ROS-induced oxidative stress in in vitro model of AMI. The activation of miR-18a reversed the effects of CASC2 on ROS-induced oxidative stress in in vitro model of AMI. These data for the first time suggest that lncRNA CASC2 have better protective effects on AMI, which could reduce oxidative stress through their carried miR-18a and subsequently downregulating the SIRT2/ROS pathway.

Exosomal LINC01005 derived from oxidized low-density lipoprotein-treated endothelial cells regulates vascular smooth muscle cell phenotypic switch.

Phenotype switch of vascular smooth muscle cells (VSMCs) plays an important role in the development of atherosclerosis (AS). Endothelial cells can regulate VSMC phenotypic switch by secreting exosomes, crucial mediators of intracellular communication. This study aimed to determine whether exosomal LINC01005 from oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs) plays a role in regulating VSMC phenotypic switch and to validate the underlying molecular mechanism. Exosomes were extracted from ox-LDL-treated HUVECs (ox-LDL-Exo) and then administered into VSMCs. VSMC phenotypic switch was assessed by determining VSMC phenotypic markers using western blot. VSMC cell proliferation and migration were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and wound healing assay, respectively. The interaction between miR-128-3p and LINC01005 or Krüppel-like factor 4 (KLF4) was analyzed by luciferase reporter assay. ox-LDL-Exo contained high expression of LINC01005. Inhibition of LINC01005 expression in ox-LDL-Exo abrogated the ox-LDL-Exo-induced VSMC phenotypic switch, proliferation, and migration. Furthermore, LINC01005 acted as a sponge of miR-128-3p to upregulate KLF4 expression. Moreover, miR-128-3p overexpression and KLF4 silencing in VSMCs attenuated the ox-LDL-Exo-induced VSMC phenotypic switch, proliferation, and migration. Collectively, exosomal LINC01005 from ox-LDL-treated HUVECs promotes VSMC phenotype switch, proliferation, and migration by regulating the miR-128-3p/KLF4 axis.