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Cardiovascular Research Advance Access first published online on October 19, 2009
This version [Corrected Proof] published online on November 12, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp341
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org
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Fractalkine has anti-apoptotic and proliferative effects on human vascular smooth muscle cells via epidermal growth factor receptor signalling

Gemma E. White1, Thomas C.C. Tan1, Alison E. John1,3, Carl Whatling2, William L. McPheat2 and David R. Greaves1,*

1 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
2 Bioscience Department, CVGI, AstraZeneca R&D Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden
3 Division of Respiratory Medicine, University of Nottingham, Centre for Respiratory Research, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, UK

* Corresponding author. Tel: +44 1865 285519, Fax: +44 1865 275515, Email: david.greaves{at}path.ox.ac.uk

Aims: Fractalkine (CX3CL1) is a membrane-bound chemokine that signals through the G protein-coupled receptor CX3CR1 that is implicated in the development of atherosclerosis. We have previously reported that CX3CR1 is expressed by primary human coronary artery smooth muscle cells (CASMC), where it mediates chemotaxis towards CX3CL1. We sought to determine the effect of CX3CL1 on CASMC survival and proliferation and elucidate the signalling mechanisms involved.

Methods and results: CX3CL1 significantly reduces staurosporine-induced apoptosis of CASMC, as quantified by caspase 3 immunostaining and Annexin-V flow cytometry. Furthermore, CX3CL1 is a potent mitogen for primary CASMC and induces phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, measured by western blotting. Inhibition of either ERK or phosphoinositide 3-kinase (PI3K) signalling abrogates proliferation, while only PI3K signalling is involved in the anti-apoptotic effects of CX3CL1. We describe a novel and specific small molecule antagonist of CX3CR1 (AZ12201182) which abrogates the mitogenic and anti-apoptotic effects of CX3CL1 on CASMC. Pharmacological inhibition of the epidermal growth factor receptor (EGFR) blocks CASMC survival and DNA synthesis, indicating a previously undocumented role for EGFR signalling in response to CX3CL1 involving release of a soluble EGFR ligand. Specifically, CX3CL1 induces shedding of epiregulin and increases epiregulin mRNA expression 20-fold within 2 h. Finally, antibody neutralization of epiregulin abrogates the mitogenic effect of CX3CL1.

Conclusion: We have demonstrated two novel and important functions of CX3CL1 on primary human SMCs: anti-apoptosis and proliferation, both mediated via epiregulin-induced EGFR signalling. Our data have important implications in vascular pathologies including atherosclerosis, restenosis, and transplant accelerated arteriosclerosis, where the balance of SMC proliferation and apoptosis critically determines both plaque stability and vessel stenosis.

KEYWORDS Smooth muscle cell; Proliferation; Anti-apoptosis; Chemokine; Fractalkine; EGFR; Epiregulin; CX3CR1; CX3CL1

Time for primary review: 18 days


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