Vascular smooth muscle cells display another colour of Cezanne’s palette

This editorial refers to ‘Cezanne is a critical regulator of pathological arterial remodelling by targeting β-catenin signalling’ by W. An et al., pp. 666--681. In the ageing vasculature, a lifetime of small dysregulations and excesses will translate into pathological thickening of the arteries and atherosclerotic plaque buildup. Vascular smooth muscle cell (VSMC) dedifferentiation, proliferation, and migration characterize these states and contributes significantly to the evolution of disease. Perhaps the most striking manifestation of this VSMC transformation occurs in the setting of restenosis. Within months of angioplasty, the ballooned vessel may reach life-threatening occlusion due to excess cell buildup, encroaching on the vascular lumen. Angioplasty with drug-coated balloons and fitting of second-generation drug-eluting stents have diminished this issue to a great extent, yet restenosis remains an issue. Even with drug-eluting stents, which are moderately more effective than drug-coated balloons,1 target lesion revascularization is required in 7–10% of patients within 5 years2 and 20% of patients after 10 years.3 This therapeutic challenge has long been tantalizing researchers. A recent study has added another piece to the VSMC dysregulation puzzle. An et al.4 report a new role for the deubiquitylating enzyme Cezanne (cellular zinc finger anti-NF-κB/OTUD7B), demonstrating its regulatory effects on VSMC proliferation and migration. Cezanne over-expression activates β-catenin signalling by targeting it for deubiquitination, and β-catenin in turn binds the CCN family number 1 (CCN1) promoter, increasing gene expression (Figure 1). Conversely, CCN1 is the most significantly down-regulated gene in VSMCs lacking Cezanne. The authors substantiate their findings in two murine models. First, endothelial denudation of the femoral arteries leads to heightened Cezanne expression, paralleling observations in human diseased vessels. Silencing Cezanne by shRNA lentiviral particle infusion abates both the relative expression of β-catenin and CCN1, and the neointimal thickening and VSMC proliferation due to injury. Second, low-density lipoprotein receptor knockout mice (LDLR−/−) are fed a high-fat diet to instigate atherosclerotic plaque development. After 12 weeks, lesions in Cezanne double knockout mice (Cez−/−/LDLR−/−) are smaller than in the Cez+/+/LDLR−/− littermates, although they bear the compositional hallmarks of a less stable plaque. Activation of Cezanne following arterial denudation or high-fat diet leads to the deubiquitination of β-catenin and increased gene expression of CCN1. This results in VSMC proliferation that amplifies neointimal thickening and progression of atherosclerosis. In the absence of Cezanne, β-catenin is targeted to the proteasome, gene expression of CCN1 is reduced, and VSMC proliferation is abated. As a result, neointimal remodelling is more modest and animals form smaller but less stable atherosclerotic plaques. Activation of Cezanne following arterial denudation or high-fat diet leads to the deubiquitination of β-catenin and increased gene expression of CCN1. This results in VSMC proliferation that amplifies neointimal thickening and progression of atherosclerosis. In the absence of Cezanne, β-catenin is targeted to the proteasome, gene expression of CCN1 is reduced, and VSMC proliferation is abated. As a result, neointimal remodelling is more modest and animals form smaller but less stable atherosclerotic plaques. This is not the first incursion of deubiquitinase research in the realm of vascular remodelling of course, but the field remains mostly unexplored. Interestingly, the very choice of mouse predominantly used for cardiovascular research may hinge on a deubiquitinase of the same family as Cezanne, A20. Quantitative trait locus mapping of intercrosses between atherosclerosis-sensitive apolipoprotein E-deficient (ApoE−/−) C57BL/6 (B6) and atherosclerosis-resistant ApoE−/− FVB mice identified the deubiquitinase A20 within an atherosclerosis-susceptibility locus. A20 haploinsufficient mice correlated with increased expression of pro-atherosclerotic NF-κB target genes.5 A20 was already known to modulate VSMC proliferation and not only to abate restenosis but to actually induce regression of intimal hyperplasia.6 So, it is understood that deubiquitinases could be exploited to the benefit of patients with cardiovascular diseases. In fact, a recent review delineates their role in inflammation, apoptosis and oxidative stress related to vascular pathologies including atherosclerosis, aneurysm, and hypertension.7 Proliferation of local VSMC accounts for a significant proportion of nascent atherosclerotic lesions cells and may even help explain their anatomical localization,8 justifying the potential for Cezanne-based therapy even in the absence of overt anti-inflammatory effects in these cells. Cezanne reportedly acts via β-catenin-dependent regulation of CCN1. Both molecules were independently shown to be strong inducers of VSMC proliferation and neointimal hyperplasia.9,10 Importantly, a tamoxifen-inducible and tissue-specific approach was used to show that VSMC β-catenin is required for neointimal lesion formation after vascular injury in adult mice.9 This nuance is lacking in the publication by An et al.,4 where a whole body knockdown of Cezanne was used instead. Hence in considering the reduced atherosclerotic plaques in Cez−/−/LDLR−/− compared with Cez+/+/LDLR−/−, it is impossible to discount a role for endothelial or immune cells. The team correctly point out that Cezanne is strongly expressed in endothelial cells and that absence of Cezanne in these cells may account for abated atherogenesis.4 The authors previously reported that although Cezanne had only had modest effects on NF-κB activation by low shear stress, it could prevent NF-κB activation downstream from tumour necrosis factor or interleukin-1 receptor signalling.11 What may also be impactful is the effect of CCN1, which stimulates both angiogenesis and endothelial regeneration.12 Thus, secreted locally within the plaque, CNN1 could both stimulate destabilizing neovessel formation and facilitate wound healing post-angioplasty. Ultimately, what will be most important will be to determine if Cezanne has what it takes to set it apart as a viable drug target. Could inhibiting this enzyme complement or outdo the current standard of care? Does the distinct cell and context-specific nature of Cezanne constitute a limitation or a strength? For now, those questions remain unanswered. But the work by An et al. provide compelling evidence that Cezanne has potential to rise to the challenge of limiting VSMC proliferation and associated vascular disease. Conflict of interest: none declared. This work is supported by funding from the Canadian Institutes for Health Research (CIHR PJT-142479 and PJT-162115). The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.