PMID- 35035663 OWN - NLM STAT- MEDLINE DCOM- 20220304 LR - 20220304 IS - 1942-0994 (Electronic) IS - 1942-0900 (Print) IS - 1942-0994 (Linking) VI - 2022 DP - 2022 TI - The TBX1/miR-193a-3p/TGF-beta2 Axis Mediates CHD by Promoting Ferroptosis. PG - 5130546 LID - 10.1155/2022/5130546 [doi] LID - 5130546 AB - 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-beta2 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-beta2 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-beta2 axis was found to promote ferroptosis based on assessments of lipid reactive oxygen species (ROS) levels, Fe(2+) 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-beta2 levels were high in human embryonic CHD tissues, as indicated by the H9c2 cell experiments. In summary, the TBX1/miR-193a-3p/TGF-beta2 axis mediates CHD by inducing ferroptosis in cardiomyocytes. TGF-beta2 may be a target gene for CHD diagnosis and treatment in children. CI - Copyright (c) 2022 Li Zhong et al. FAU - Zhong, Li AU - Zhong L AUID- ORCID: 0000-0002-0858-7139 AD - Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Yang, Huiqin AU - Yang H AUID- ORCID: 0000-0002-8246-5260 AD - Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Zhu, Binlu AU - Zhu B AUID- ORCID: 0000-0001-6152-843X AD - Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. FAU - Zhao, Xueqi AU - Zhao X AUID- ORCID: 0000-0002-7925-0752 AD - Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Xie, Meijun AU - Xie M AUID- ORCID: 0000-0001-5040-5784 AD - Department of Pediatric Cardiology, Zhengzhou University Third Hospital and Henan Province Women and Children's Hospital, Zhengzhou, Nan He, China. FAU - Cao, Meiling AU - Cao M AUID- ORCID: 0000-0002-0430-0858 AD - Department of Neonatology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Liu, Chang AU - Liu C AUID- ORCID: 0000-0002-3235-9574 AD - Department of Pediatrics, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Zhao, Danyang AU - Zhao D AUID- ORCID: 0000-0002-9589-1437 AD - Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Lyu, Yuan AU - Lyu Y AUID- ORCID: 0000-0002-9752-9220 AD - Department of Gynecology and Obstetrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. FAU - Shang, Weiguang AU - Shang W AUID- ORCID: 0000-0003-2229-0136 AD - Department of Pediatrics, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning, China. FAU - Wang, Bo AU - Wang B AUID- ORCID: 0000-0002-2850-7634 AD - Department of Pediatrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. FAU - Wu, Ying AU - Wu Y AUID- ORCID: 0000-0002-7930-2399 AD - Department of Pediatrics, Shenyang Children's Hospital, Shenyang, Liaoning, China. FAU - Sun, Xiuju AU - Sun X AUID- ORCID: 0000-0001-5451-1541 AD - Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China. FAU - Qiu, Guangrong AU - Qiu G AUID- ORCID: 0000-0003-3789-8603 AD - Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China. FAU - Fu, Weineng AU - Fu W AUID- ORCID: 0000-0002-0599-1021 AD - Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China. FAU - Jiang, Hongkun AU - Jiang H AUID- ORCID: 0000-0002-2733-898X AD - Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. LA - eng PT - Journal Article DEP - 20220107 PL - United States TA - Oxid Med Cell Longev JT - Oxidative medicine and cellular longevity JID - 101479826 RN - 0 (T-Box Domain Proteins) RN - 0 (TBX1 protein, human) RN - 0 (TGFB2 protein, human) RN - 0 (Transforming Growth Factor beta2) SB - IM MH - Ferroptosis/*genetics MH - HEK293 Cells MH - Heart Defects, Congenital/*genetics MH - Humans MH - T-Box Domain Proteins/*metabolism MH - Transfection MH - Transforming Growth Factor beta2/*metabolism PMC - PMC8759832 COIS- All the authors of this paper declare no conflicts of interest. EDAT- 2022/01/18 06:00 MHDA- 2022/03/05 06:00 PMCR- 2022/01/07 CRDT- 2022/01/17 05:57 PHST- 2021/07/22 00:00 [received] PHST- 2021/11/24 00:00 [revised] PHST- 2021/12/06 00:00 [accepted] PHST- 2022/01/17 05:57 [entrez] PHST- 2022/01/18 06:00 [pubmed] PHST- 2022/03/05 06:00 [medline] PHST- 2022/01/07 00:00 [pmc-release] AID - 10.1155/2022/5130546 [doi] PST - epublish SO - Oxid Med Cell Longev. 2022 Jan 7;2022:5130546. doi: 10.1155/2022/5130546. eCollection 2022.