Loss of OTUD6B Stimulates Angiogenesis and Promotes Diabetic Atherosclerosis

Zhongqun Wang; Lili Zhang; Lihua Li; Mengxue Zhou

doi:10.2147/DMSO.S380986

Loss of OTUD6B Stimulates Angiogenesis and Promotes Diabetic Atherosclerosis

Diabetes Metab Syndr Obes. 2022 Sep 28:15:3027-3038. doi: 10.2147/DMSO.S380986. eCollection 2022.

Authors

Zhongqun Wang^#¹, Lili Zhang^#¹, Lihua Li², Mengxue Zhou¹

Affiliations

¹ Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People's Republic of China.
² Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Angiogenesis is an essential promoter of atherosclerotic plaque rupture. However, the mechanism of its regulation is not understood. OTUD6B regulates cell proliferation, migration, and angiogenesis. We investigated the role of OTUD6B in angiogenesis in diabetic atherosclerotic plaques.

Patients and methods: The expression of OTUD6B was analyzed by single cell RNA sequencing (scRNA-seq) and RNA sequencing (RNA-seq) and evaluated by Immunofluorescence in human anterior tibial arteries from diabetic amputees and ApoE^-/- mice. Furthermore, we constructed a mouce model of diabetic atherosclerosis and used the mice to study the effect of OTUD6B downregulation in vivo by injecting them with AAV-shOTUD6B. Mouse brain microvascular endothelial cells (MBVECs) were treated with normal glucose and high lipid (NG/HL) or high glucose and high lipid (HG/HL), and siOTUD6B was used to investigate the effect of OTUD6B on proliferation, migration, and lumen formation of endothelial cells.

Results: We found that OTUD6B expression was markedly downregulated in human anterior tibial arteries from diabetic amputees and ApoE^-/- mice. The silencing of OTUD6B resulted in diabetic atherosclerotic mice plaque instability and increased angiogenesis. In addition, the silencing of OTUD6B expression enhanced the proliferation, migration, and lumen formation of endothelial cells.

Conclusion: OTUD6B can reduce angiogenesis in atherosclerotic plaques, enhance plaque stability and delay the progression of atherosclerosis by regulating the proliferation, migration, and lumen formation of endothelial cells.

Keywords: OTUD6B; angiogenesis; atherosclerosis; diabetes.

Grants and funding

This work was supported by the National Natural Science Foundation of China (82070455); the related Foundation of Jiangsu Province (BK20201225, M2020016); Medical Innovation Team Project of Jiangsu Province (CXTDA2017010); the Open Project Program of Guangxi Key Laboratory of Centre of Diabetic Systems Medicine (GKLCDSM-20210101-02).