Fractalkine has anti-apoptotic and proliferative effects on human vascular smooth muscle cells via epidermal growth factor receptor signalling.Report as inadecuate




Fractalkine has anti-apoptotic and proliferative effects on human vascular smooth muscle cells via epidermal growth factor receptor signalling. - Download this document for free, or read online. Document in PDF available to download.

Reference: White, GE, Tan, TC, John, AE et al., (2010). Fractalkine has anti-apoptotic and proliferative effects on human vascular smooth muscle cells via epidermal growth factor receptor signalling. Cardiovascular research, 85 (4), 825-835.Citable link to this page:

 

Fractalkine has anti-apoptotic and proliferative effects on human vascular smooth muscle cells via epidermal growth factor receptor signalling.

Abstract: 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.

Publication status:Published

Bibliographic Details

Journal: Cardiovascular researchsee more from them

Issue Date: 2010-3

pages:825-835Identifiers

Urn: uuid:fa1e9f7a-d56c-4c1f-b9be-b4f84237ed17

Source identifier: 12746

Eissn: 1755-3245

Doi: https://doi.org/10.1093/cvr/cvp341

Issn: 0008-6363 Item Description

Type: Journal article;

Language: eng Keywords: Humans Coronary Vessels Cells, Cultured Extracellular Signal-Regulated MAP Kinases Receptor, Epidermal Growth Factor Mitogens Signal Transduction Phosphorylation Cell Division Apoptosis Gene Expression Atherosclerosis Chemokine CX3CL1 Muscle, Smooth, Vascular Phosphatidylinositol 3-Kinases Epidermal Growth Factor Proto-Oncogene Proteins c-akt Tiny URL: pubs:12746

Relationships





Author: White, GE - institutionUniversity of Oxford Oxford, MSD, Pathology Dunn School - - - Tan, TC - - - John, AE - - - Whatling, C - -

Source: https://ora.ox.ac.uk/objects/uuid:fa1e9f7a-d56c-4c1f-b9be-b4f84237ed17



DOWNLOAD PDF




Related documents