4.6 Review

Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications

Journal

NATURE REVIEWS CARDIOLOGY
Volume 19, Issue 12, Pages 783-797

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41569-022-00718-5

Keywords

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Funding

  1. British Heart Foundation [CH/F/21/90009, TG/19/2/34831, RG/F/21/110040]
  2. Oxford BHF Centre of Research Excellence [RE/18/3/34214]
  3. Oxford NIHR Biomedical Research Centre

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Non-canonical WNT signaling plays an important role in cardiovascular diseases such as atherosclerosis, heart failure, and arrhythmias. This review provides an overview of non-canonical WNT signaling, describes its links to the pathogenesis of these cardiovascular diseases, and explores the clinical potential of targeting individual components of non-canonical WNT signaling for their treatment.
WNT signalling comprises a diverse spectrum of receptor-mediated pathways activated by a large family of WNT ligands and influencing fundamental biological processes. WNT signalling includes the beta-catenin canonical pathway and the non-canonical pathways, namely the planar cell polarity and the calcium-dependent pathways. Advances over the past decade have linked non-canonical WNT signalling with key mechanisms of atherosclerosis, including oxidative stress, endothelial dysfunction, macrophage activation and vascular smooth muscle cell phenotype regulation. In addition, non-canonical WNT signalling is involved in crucial aspects of myocardial biology, from fibrosis to hypertrophy and oxidative stress. Importantly, non-canonical WNT signalling activation has complex effects in adipose tissue in the context of obesity, thereby potentially linking metabolic and vascular diseases. Tissue-specific targeting of non-canonical WNT signalling might be associated with substantial risks of off-target tumorigenesis, challenging its therapeutic potential. However, novel technologies, such as monoclonal antibodies, recombinant decoy receptors, tissue-specific gene silencing with small interfering RNAs and gene editing with CRISPR-Cas9, might enable more efficient therapeutic targeting of WNT signalling in the cardiovascular system. In this Review, we summarize the components of non-canonical WNT signalling, their links with the main mechanisms of atherosclerosis, heart failure and arrhythmias, and the rationale for targeting individual components of non-canonical WNT signalling for the treatment of cardiovascular disease. In this Review, the authors discuss the roles of non-canonical WNT signalling in cardiovascular disease. They provide an overview of non-canonical WNT signalling, describe its links to the pathogenesis of atherosclerosis, heart failure and arrhythmias, and explore the clinical potential of targeting individual components of non-canonical WNT signalling in cardiovascular disease.

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