The TBX1/miR-193a-3p/TGF-β2 Axis Mediates CHD by Promoting Ferroptosis

Abstract

Congenital heart disease (CHD) is the most common noninfectious cause of death during the neonatal stage. T-box transcription factor 1 (TBX1) is the main genetic determinant of 22q11.2 deletion syndrome (22q11.2DS), which is a common cause of CHD. Moreover, ferroptosis is a newly discovered kind of programmed cell death. In this study, the interaction among TBX1, miR-193a-3p, and TGF-β2 was tested using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and dual-luciferase reporter assays. TBX1 silencing was found to promote TGF-β2 messenger ribonucleic acid (mRNA) and protein expression by downregulating the miR-193a-3p levels in H9c2 cells. In addition, the TBX1/miR-193a-3p/TGF-β2 axis was found to promote ferroptosis based on assessments of lipid reactive oxygen species (ROS) levels, Fe2+ concentrations, mitochondrial ROS levels, and malondialdehyde (MDA) contents; Cell Counting Kit-8 (CCK-8) assays and transmission electron microscopy; and Western blotting analysis of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), NADPH oxidase 4 (NOX4), and acyl-CoA synthase long-chain family member 4 (ACSL4) protein expression. The protein expression of NRF2, GPX4, HO-1, NOX4, and ACSL4 and the level of MDA in human CHD specimens were also detected. In addition, TBX1 and miR-193a-3p expression was significantly downregulated and TGF-β2 levels were high in human embryonic CHD tissues, as indicated by the H9c2 cell experiments. In summary, the TBX1/miR-193a-3p/TGF-β2 axis mediates CHD by inducing ferroptosis in cardiomyocytes. TGF-β2 may be a target gene for CHD diagnosis and treatment in children.

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis

“…NOX4 is the major oxidase for ROS production in cardiac mitochondria, and its expression is significantly elevated in the DIC model [35]. High NOX4 expression is positively correlated with ferroptosis [36]. In this study, dioscin inhibited DOX-promoted NOX4 expression and mitochondrial ROS levels.…”

Exposure to essential and non-essential trace elements and risks of congenital heart defects: A narrative review

“…Ferroptosis is a new form of regulated cell death characterized with Fe overload and lipid peroxidation, and may play pathogenetic roles in cardiovascular diseases ( 109 ). A recent study initially uncovered the potential role of ferroptosis in CHDs ( 110 ). In this study, gene silencing of T-box transcription factor 1 (TBX1), the candidate disease-causing gene of DiGeorge syndrome (also known as velo-cardio-facial syndrome), led to elevated ferroptosis in embryonic cardiomyocyte cell line H9c2.…”

Identifying miRNA-mRNA regulatory networks on extreme n-6/n-3 polyunsaturated fatty acid ratio expression profiles in porcine skeletal muscle

“…In addition, GWAS analyses in human metabolic syndrome discovered the association of the strawberry notch homolog 1 ( SBNO1 ) gene on plasma high-density lipoprotein cholesterol concentration, whereas the vestigial like family member 2 ( VGLL2 ) gene was linked to the fatty acids profile in sheep [ 41 , 42 ]. The T-box transcription factor 1 ( TBX1 ) gene, together with miR-193a-3p / TGF-β2 , was found to drive iron-dependent cell death ferroptosis through the accumulation of lipid peroxides in neonates [ 43 , 44 ]. Abundancy on n-3 PUFA in cattle is reported to increase the gene expression of insulin-like growth factors such as the insulin-like growth factor binding protein 5 ( IGFBP-5 ) and further influence reproductive performance [ 45 ].…”