Cezanne is a critical regulator of pathological arterial remodelling by targeting β-catenin signalling

Author:

An Weiwei1,Luong Le A1,Bowden Neil P2,Yang Mei13,Wu Wei1,Zhou Xinmiao1,Liu Chenxin1ORCID,Niu Kaiyuan1,Luo Jun1,Zhang Cheng1,Sun Xiaolei1ORCID,Poston Robin4ORCID,Zhang Li3,Evans Paul C2,Xiao Qingzhong156ORCID

Affiliation:

1. Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK

2. Department of Infection, Immunity and Cardiovascular Disease, Bateson Centre, and Insigneo Institute for In Silico Medicine, University of Sheffield, Beech Hill Rd, Sheffield S10 2RX, UK

3. Department of Cardiology, and Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

4. Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

5. Key Laboratory of Cardiovascular Diseases at The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China

6. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China

Abstract

Abstract Aims Pathological arterial remodelling including neointimal hyperplasia and atherosclerosis is the main underlying cause for occluding arterial diseases. Cezanne is a novel deubiquitinating enzyme, functioning as a NF-кB negative regulator, and plays a key role in renal inflammatory response and kidney injury induced by ischaemia. Here we attempted to examine its pathological role in vascular smooth muscle cell (VSMC) pathology and arterial remodelling. Methods and results Cezanne expression levels were consistently induced by various atherogenic stimuli in VSMCs, and in remodelled arteries upon injury. Functionally, VSMCs over-expressing wild-type Cezanne, but not the mutated catalytically-inactive Cezanne (C209S), had an increased proliferative ability and mobility, while the opposite was observed in VSMCs with Cezanne knockdown. Surprisingly, we observed no significant effects of Cezanne on VSMC apoptosis, NF-κB signalling, or inflammation. RNA-sequencing and biochemical studies showed that Cezanne drives VSMC proliferation by regulating CCN family member 1 (CCN1) by targeting β-catenin for deubiquitination. Importantly, local correction of Cezanne expression in the injured arteries greatly decreased VSMC proliferation, and prevented arterial inward remodelling. Interestingly, global Cezanne gene deletion in mice led to smaller atherosclerotic plaques, but with a lower level of plaque stability. Translating, we observed a similar role for Cezanne in human VSMCs, and higher expression levels of Cezanne in human atherosclerotic lesions. Conclusion Cezanne is a key regulator of VSMC proliferation and migration in pathological arterial remodelling. Our findings have important implications for therapeutic targeting Cezanne signalling and VSMC pathology in vascular diseases.

Funder

British Heart Foundation

National Institute for Health Research Biomedical Research Centre at Barts

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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