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

Area of Science:

• Vascular Biology
• Molecular Medicine
• Biochemistry

Background:

• Pathological arterial remodelling, including neointimal hyperplasia and atherosclerosis, underlies occlusive arterial diseases.
• Cezanne, a deubiquitinating enzyme and NF-κB negative regulator, is involved in renal inflammatory responses and kidney injury.

Purpose of the Study:

• To investigate the pathological role of Cezanne in vascular smooth muscle cell (VSMC) pathology and arterial remodelling.
• To explore Cezanne's function in the context of atherosclerosis and vascular disease.

Main Methods:

• Examined Cezanne expression in VSMCs and remodelled arteries under atherogenic stimuli and injury.
• Assessed VSMC proliferation, mobility, and apoptosis with altered Cezanne levels (over-expression, knockdown, catalytic mutants).
• Utilized RNA-sequencing and biochemical assays to identify Cezanne's molecular targets (CCN1, β-catenin) and signalling pathways.

Main Results:

• Cezanne expression was induced by atherogenic stimuli and injury in VSMCs and arteries.
• Over-expression of wild-type Cezanne increased VSMC proliferation and migration; knockdown decreased these.
• Cezanne regulates VSMC proliferation via CCN1 and β-catenin deubiquitination, independent of NF-κB signalling or apoptosis.
• Local Cezanne correction reduced VSMC proliferation and arterial remodelling in vivo.
• Global Cezanne deletion in mice resulted in smaller atherosclerotic plaques with reduced stability.
• Cezanne plays a similar role in human VSMCs and is upregulated in human atherosclerotic lesions.

Conclusions:

• Cezanne is a critical regulator of VSMC proliferation and migration in pathological arterial remodelling.
• Findings suggest Cezanne signalling as a potential therapeutic target for vascular diseases.
• Understanding Cezanne's role in VSMC pathology is crucial for developing new vascular disease treatments.