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.
Highlights
Congenital heart disease (CHD), a congenital malformation caused by abnormal growth of the heart and great vessels during the fetal period, is the main noninfectious cause of death during the neonatal stage
We found by microarray analysis that TGF-β2 expression in TBX1-silenced cardiomyocytes was significantly upregulated (Table S5)
The messenger ribonucleic acid (mRNA) and protein expression levels of TGFβ2 were raised in the TBX1 Small Interfering RNA (siRNA) group (P < 0:05) (Figures 1(a) and 1(b))
Summary
Congenital heart disease (CHD), a congenital malformation caused by abnormal growth of the heart and great vessels during the fetal period, is the main noninfectious cause of death during the neonatal stage. The average global prevalence of CHD is 9.410‰. In China, the prevalence of CHD has reached 4.905‰ [1, 2]. Oxidative Medicine and Cellular Longevity births, 8 infants suffer from CHD. A Norwegian study showed that the survival rate of patients with complex coronary heart disease by the age of 16 was 87% from 1990 to 2011; that is, the mortality of patients with CHD decreased significantly. This research was aimed at offering new ideas for CHD diagnosis and treatment in children
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