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UFM1 inhibits hypoxia-induced angiogenesis via promoting proteasome degradation of HIF-1α

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Abstract

Angiogenesis is crucial for blood flow recovery and ischemic tissue repair of peripheral artery disease (PAD). Exploration of new mechanisms underlying angiogenesis will shed light on the treatment of PAD. Ubiquitin-fold modifier 1 (UFM1), a newly identified ubiquitin-like molecule, has been discovered to be involved in various pathophysiological processes. However, the role of UFM1 in the pathogenesis of PAD, especially in endothelial angiogenesis remains obscure, and we aimed to clarify this issue in this study. We initially found UFM1 was significantly upregulated in gastrocnemius muscles of PAD patients and hind limb ischemia mice. And UFM1 was mainly colocalized with endothelial cells in ischemic muscle tissues. Further, elevated expression of UFM1 was observed in hypoxic endothelial cells. Subsequent genetic inhibition of UFM1 dramatically enhanced migration, invasion, adhesion, and tube formation of endothelial cells under hypoxia. Mechanistically, UFM1 reduced the stability of hypoxia-inducible factor-1α (HIF-1α) and promoted the von Hippel–Lindau-mediated K48-linked ubiquitin–proteasome degradation of HIF-1α, which in turn decreased angiogenic factor VEGFA expression and suppressed VEGFA related signaling pathway. Consistently, overexpression of UFM1 inhibited the angiogenesis of endothelial cells under hypoxic conditions, whereas overexpression of HIF-1α reversed this effect. Collectively, our data reveal that UFM1 inhibits the angiogenesis of endothelial cells under hypoxia through promoting ubiquitin–proteasome degradation of HIF-1α, suggesting UFM1 might serve as a potential therapeutic target for PAD.

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Acknowledgements

We would like to acknowledge Professor Huaidong Song from the Core Laboratory in Medical Center of Clinical Research of Shanghai Ninth People’s Hospital affiliated with Shanghai Jiao Tong University School of Medicine. The schematic illustration was drawn with Figdraw.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Number 82000258 and 81670735), Natural Science Foundation of Shanghai (Grant Number 22ZR1436500). Shanghai Ninth People’s Hospital Foundation, Shanghai JiaoTong University School of Medicine (Grant Number JYLJ201921, JYHJB04 and JYZP003).

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  1. Yu Jing and Kuanping Ye have contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, 280 Mohe Road, Shanghai, 201999, China

    Yu Jing, Kuanping Ye, Jing Zhu, Ziming Mao, Qianru Zhang & Fengling Chen

  2. Department of Cardiology, Shanghai Sixth People’s Hospital, Shanghai JiaoTong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China

    Guangya Zhang

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Contributions

Yu Jing: Conceptualization, Software, Investigation, Resources, Writing—original draft, Writing—review & editing, Visualization. Kuanping Ye: Methodology, Software, Investigation, Data curation, Writing—review & editing. Guangya Zhang: Methodology, Validation, Funding acquisition. Jing Zhu: Validation, Data curation. Ziming Mao: Validation, Formal analysis. Qianru Zhang: Formal analysis. Fengling Chen: Conceptualization, Supervision, Project administration, funding acquisition. All authors have read and agreed to the published version of the manuscript.

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Jing, Y., Ye, K., Zhang, G. et al. UFM1 inhibits hypoxia-induced angiogenesis via promoting proteasome degradation of HIF-1α. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-05013-0

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