Upregulation of Long Noncoding RNA MAGOH-DT Mediates TNF-<i>α</i> and High Glucose-Induced Endothelial-Mesenchymal Transition in Arteriosclerosis Obliterans

Upregulation of Long Noncoding RNA MAGOH-DT Mediates TNF-α and High Glucose-Induced Endothelial-Mesenchymal Transition in Arteriosclerosis Obliterans

Kang-Jie Wang,^1,2,3 Yi-Xin Zhang,^2,4 Zhi-Wei Mo,^1,2,3 Zi-Lun Li,^1,2,3 Mian Wang,^1,2,3 Rui Wang,¹^,2,³ Zhe-Cun Wang,^1,2,3 Guang-Qi Chang^1,2,3 and Wei-Bin Wu^1,2,3

¹Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guandong, P.R. China
²National-Local Joint Engineering Laboratory of Vascular Diseases Treatment, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Gunadong, P.R. China
³Guangdong Engineering Laboratoty of Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guandong, P.R. China
⁴Division of Hypertension and Vascular Diseases, Department of Cardiology, Heart Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guandong, P.R. China

Arteriosclerosis obliterans (ASO) is characterized by arterial narrowing and blockage due to atherosclerosis, influenced by endothelial dysfunction and inflammation. This research focuses on exploring the role of MAGOH-DT, a long noncoding RNA, in mediating endothelial cell dysfunction through endothelial-mesenchymal transition (EndMT) under inflammatory and hyperglycemic stimuli, aiming to uncover potential therapeutic targets for ASO. Differential expression of lncRNAs, including MAGOH-DT, was initially identified in arterial tissues from ASO patients compared to healthy controls through lncRNA microarray analysis. Validation of MAGOH-DT expression in response to tumor necrosis factor-alpha (TNF-α) and high glucose (HG) was performed in human umbilical vein endothelial cells (HUVECs) using RT-qPCR. The effects of MAGOH-DT and HNRPC knockdown on EndMT were assessed by evaluating EndMT markers and TGF-β2 protein expression with Western blot analysis. RNA-immunoprecipitation assays were used to explore the interaction between MAGOH-DT and HNRPC, focusing on their role in regulating TGF-β2 translation. In the results, MAGOH-DT expression is found to be upregulated in ASO and further induced in HUVECs under TNF-α/HG conditions, contributing to the facilitation of EndMT. Silencing MAGOH-DT or HNRPC is shown to inhibit the TNF-α/HG-induced increase in TGF-β2 protein expression, effectively attenuating EndMT processes without altering TGF-β2 mRNA levels. In conclusion, MAGOH-DT is identified as a key mediator in the process of TNF-α/HG-induced EndMT in ASO, offering a promising therapeutic target. Inhibition of MAGOH-DT presents a novel therapeutic strategy for ASO management, especially in cases complicated by diabetes mellitus. Further exploration into the therapeutic implications of MAGOH-DT modulation in ASO treatment is warranted.

Key words —— arteriosclerosis obliterans; diabetes mellitus; endothelial-mesenchymal transition; inflammation; long noncoding RNA

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Tohoku J. Exp. Med., 2024 August, 263(4), 227-238.

*These authors contributed equally to this work.

Correspondence: Wei-Bin Wu, M.D., Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhong Shan Er Road, Guangzhou, Guandong 510080, P.R. China.

e-mail: wuweib@mail2.sysu.edu.cn, wuweibsysu@163.com

Correspondence: Guang-Qi Chang, M.D., Ph.D., Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhong Shan Er Road, Guangzhou, Guandong 510080, P.R.China.

e-mail: changgq@mail.sysu.edu.cn