Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRβ

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外文摘要：Atherosclerosis is a chronic artery disease that causes various types of cardiovascular dysfunction.Vascular smooth muscle cells(VSMCs),the main components of atherosclerotic plaque,switch from contractile to synthetic phenotypes during atherogenesis.Ubiquitylation is crucial in regulating VSMC phenotypes in atherosclerosis,and it can be reversely regulated by deubiquitinases.However,the specific effects of deubiquitinases on atherosclerosis have not been thoroughly elucidated.In this study,RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases,which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype switch.Further in vivo studies using Apoe-/-mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque phenotype.Moreover,VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in vitro.Unbiased RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation,adhesion,and proliferation.Mass spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ubiquitylated.Mechanistically,we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRβwith its catalytic triad,thereby reducing the K48-linked ubiquitylation of PDGFRβ.Inhibiting OTUB1 in VSMCs could promote PDGFRβ degradation via the ubiquitin-proteasome pathway,so it was beneficial in preventing VSMCs'phenotype switch.These findings revealed that knocking down OTUB1 ameliorated VSMCs'phenotype switch and atherosclerosis progression,indicating that OTUB1 could be a valuable translational therapeutic target in the future.

外文关键词：

atherosclerosisvascular smooth muscle cellubiquitylationdeubiquitinaseOTUB1PDGFRβ

作者：

Fei Xu、Han Chen、Changyi Zhou、Tongtong Zang、Rui Wang、Shutong Shen、Chaofu Li、Yue Yu、Zhiqiang Pei、Li Shen、Juying Qian、Junbo Ge

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作者单位：

Department of Cardiology and Laboratory of Heart Valve Disease,West China Hospital,Sichuan University,Chengdu 610041,China

Department of Cardiology,Zhongshan Hospital,Fudan University,Research Unit of Cardiovascular Techniques and Devices,Chinese Academy of Medical Sciences,Shanghai 200032,China

Shanghai Institute of Cardiovascular Diseases,Shanghai 200032,China

National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine(19MC1910300),Shanghai

National Clinical Research Center for Interventional Medicine & Shanghai Clinical Research Center for Interventional Medicine(19MC1910300),Shanghai 200032,China

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基金：

National Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShanghai Engineering Research Center of Interventional MedicineShanghai Clinical Research Center for Interventional Medicine

项目编号：

2021YFC2500500T22881018217034219DZ225030019MC1910300

出版年：

2024

DOI：

10.1007/s11684-024-1056-8

医学前沿

高等教育出版社

医学前沿

CSTPCD

影响因子：1.362

ISSN：2095-0217

年,卷(期)：2024.18(3)