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Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration
BACKGROUND AND PURPOSE: There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, as it can lead either to monocyte repulsion from or retention within plaques depending on its cellular source. We investigated the effect of aspirin, which is widely used...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507159/ https://www.ncbi.nlm.nih.gov/pubmed/25824964 http://dx.doi.org/10.1111/bph.13144 |
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author | Passacquale, Gabriella Phinikaridou, Alkystis Warboys, Christina Cooper, Margaret Lavin, Begona Alfieri, Alessio Andia, Marcelo E Botnar, Rene M Ferro, Albert |
author_facet | Passacquale, Gabriella Phinikaridou, Alkystis Warboys, Christina Cooper, Margaret Lavin, Begona Alfieri, Alessio Andia, Marcelo E Botnar, Rene M Ferro, Albert |
author_sort | Passacquale, Gabriella |
collection | PubMed |
description | BACKGROUND AND PURPOSE: There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, as it can lead either to monocyte repulsion from or retention within plaques depending on its cellular source. We investigated the effect of aspirin, which is widely used in cardiovascular prophylaxis, on the synthesis of different isoforms of netrin-1 by endothelial cells under pro-inflammatory conditions, and defined the net effect of aspirin-dependent systemic modulation of netrin-1 on atherosclerosis progression. EXPERIMENTAL APPROACH: Netrin-1 synthesis was studied in vitro using human endothelial cells stimulated with TNF-α, with or without aspirin treatment. In vivo experiments were conducted in ApoE(−/−) mice fed with a high-fat diet (HFD), receiving either aspirin or clopidogrel. KEY RESULTS: TNF-α-induced NF-κB activation up-regulated the nuclear isoform of netrin-1, while simultaneously reducing secreted netrin-1. Down-regulation of the secreted isoform compromised the chemorepellent action of the endothelium against monocyte chemotaxis. Aspirin counteracted TNF-α-mediated effects on netrin-1 synthesis by endothelial cells through COX-dependent inhibition of NF-κB and concomitant histone hyperacetylation. Administration of aspirin to ApoE(−/−) mice on HFD increased blood and arterial wall levels of netrin-1 independently of its effects on platelets, accompanied by reduced plaque size and content of monocytes/macrophages, compared with untreated or clopidogrel-treated mice. In vivo blockade of netrin-1 enhanced monocyte plaque infiltration in aspirin-treated ApoE(−/−) mice. CONCLUSIONS AND IMPLICATIONS: Aspirin counteracts down-regulation of secreted netrin-1 induced by pro-inflammatory stimuli in endothelial cells. The aspirin-dependent increase of netrin-1 in ApoE(−/−) mice exerts anti-atherogenic effects by preventing arterial accumulation of monocytes. |
format | Online Article Text |
id | pubmed-4507159 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-45071592015-12-11 Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration Passacquale, Gabriella Phinikaridou, Alkystis Warboys, Christina Cooper, Margaret Lavin, Begona Alfieri, Alessio Andia, Marcelo E Botnar, Rene M Ferro, Albert Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, as it can lead either to monocyte repulsion from or retention within plaques depending on its cellular source. We investigated the effect of aspirin, which is widely used in cardiovascular prophylaxis, on the synthesis of different isoforms of netrin-1 by endothelial cells under pro-inflammatory conditions, and defined the net effect of aspirin-dependent systemic modulation of netrin-1 on atherosclerosis progression. EXPERIMENTAL APPROACH: Netrin-1 synthesis was studied in vitro using human endothelial cells stimulated with TNF-α, with or without aspirin treatment. In vivo experiments were conducted in ApoE(−/−) mice fed with a high-fat diet (HFD), receiving either aspirin or clopidogrel. KEY RESULTS: TNF-α-induced NF-κB activation up-regulated the nuclear isoform of netrin-1, while simultaneously reducing secreted netrin-1. Down-regulation of the secreted isoform compromised the chemorepellent action of the endothelium against monocyte chemotaxis. Aspirin counteracted TNF-α-mediated effects on netrin-1 synthesis by endothelial cells through COX-dependent inhibition of NF-κB and concomitant histone hyperacetylation. Administration of aspirin to ApoE(−/−) mice on HFD increased blood and arterial wall levels of netrin-1 independently of its effects on platelets, accompanied by reduced plaque size and content of monocytes/macrophages, compared with untreated or clopidogrel-treated mice. In vivo blockade of netrin-1 enhanced monocyte plaque infiltration in aspirin-treated ApoE(−/−) mice. CONCLUSIONS AND IMPLICATIONS: Aspirin counteracts down-regulation of secreted netrin-1 induced by pro-inflammatory stimuli in endothelial cells. The aspirin-dependent increase of netrin-1 in ApoE(−/−) mice exerts anti-atherogenic effects by preventing arterial accumulation of monocytes. John Wiley & Sons, Ltd 2015-07 2015-06-04 /pmc/articles/PMC4507159/ /pubmed/25824964 http://dx.doi.org/10.1111/bph.13144 Text en Copyright © 2015 The British Pharmacological Society http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Research Papers Passacquale, Gabriella Phinikaridou, Alkystis Warboys, Christina Cooper, Margaret Lavin, Begona Alfieri, Alessio Andia, Marcelo E Botnar, Rene M Ferro, Albert Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration |
title | Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration |
title_full | Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration |
title_fullStr | Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration |
title_full_unstemmed | Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration |
title_short | Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration |
title_sort | aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507159/ https://www.ncbi.nlm.nih.gov/pubmed/25824964 http://dx.doi.org/10.1111/bph.13144 |
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