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

Nature Reviews Cardiology volume 19, pages 783–797 (2022)Cite this article

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Abstract

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 β-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.

Key points

  • Cardiovascular disease is a major cause of morbidity and mortality worldwide, prompting the need for a better understanding of the underlying pathogenic mechanisms.

  • Non-canonical WNT signalling involves an evolutionarily conserved and ubiquitous range of pathways affecting fundamental processes such as inflammation, metabolism, cell motility, oxidative stress and homeostasis.

  • Non-canonical WNT signalling is a promising target in vascular disease, influencing vascular oxidative stress, endothelial dysfunction, inflammation, vascular smooth muscle cell phenotypes and cellular insulin resistance, all of which can affect atherosclerosis progression and plaque stability.

  • Non-canonical WNT signalling has putative links to cardiac disease by influencing myocardial oxidative stress, inflammation, repair capacity, energetics and remodelling, including fibrotic or adipose infiltration of the myocardium, all of which can generate the substrate for contractile dysfunction and arrhythmogenic potential.

  • Non-canonical WNT ligands are secreted by adipose tissue and are upregulated in obesity, acting as an endocrine and paracrine link between obesity and cardiovascular complications via adipose tissue–cardiovascular system crosstalk.

  • Non-canonical WNT signalling can be therapeutically targeted at multiple levels and could involve several state-of-the-art technologies; however, more research in this area is required.

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Fig. 1: Overview of non-canonical WNT signalling pathways.
Fig. 2: Non-canonical WNT signalling in atherosclerosis.
Fig. 3: Non-canonical WNT signalling and bidirectional interactions between adipose tissue depots and the cardiovascular system.
Fig. 4: Non-canonical WNT signalling in myocardial disease.
Fig. 5: Potential strategies for therapeutic targeting of non-canonical WNT signalling.

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Acknowledgements

C.A. acknowledges support from the British Heart Foundation (CH/F/21/90009, TG/19/2/34831 and RG/F/21/110040), theOxford BHF Centre of Research Excellence (RE/18/3/34214) and the Oxford NIHR Biomedical Research Centre.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Ioannis Akoumianakis, Murray Polkinghorne & Charalambos Antoniades

  2. Acute Vascular Imaging Centre, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    Charalambos Antoniades

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  1. Ioannis Akoumianakis
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  2. Murray Polkinghorne
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I.A. and M.P. researched data for the article. I.A. and C.A. contributed to the discussion of content, and I.A. wrote the manuscript. All the authors reviewed and/or edited the manuscript before submission.

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Correspondence to Charalambos Antoniades.

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C.A. is founder, shareholder and director of Caristo Diagnostics, a CT image analysis company. The other authors declare no competing interests.

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Akoumianakis, I., Polkinghorne, M. & Antoniades, C. Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications. Nat Rev Cardiol 19, 783–797 (2022). https://doi.org/10.1038/s41569-022-00718-5

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