Loss of OTUD6B Stimulates Angiogenesis and Promotes Diabetic Atherosclerosis

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

Data Sharing Statement

All datasets supporting the conclusions of this article are included in the article.

Ethics Approval and Consent to Participate

The ethical review number of the study is ChiCTR1900025122 and was conducted in accordance with the principles of the “Helsinki Declaration”. Written informed consent was obtained from all patients. All animal experiments in this study were conducted in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No.5–23, revised 1996) and approved by the Animal Care and Use Committee of Jiangsu University, China.

Disclosure

The authors declare that there is no conflict of interest regarding the publication of this article.

Additional information

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).