title: Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Clinical Pharmacology, BHF Centre of Research Excellence, Cardiovascular Division, King's College London, London, UK.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Passacquale
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, BHF Centre of Research Excellence and the Wellcome Trust/EPSRC Medical Engineering Centre, King's College London, London, UK.
authors.forename: Alkystis
authors.initials: A
authors.lastname: Phinikaridou
authors.affiliation: Department of Clinical Pharmacology, BHF Centre of Research Excellence, Cardiovascular Division, King's College London, London, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Warboys
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, BHF Centre of Research Excellence and the Wellcome Trust/EPSRC Medical Engineering Centre, King's College London, London, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Cooper
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, BHF Centre of Research Excellence and the Wellcome Trust/EPSRC Medical Engineering Centre, King's College London, London, UK.
authors.forename: Begona
authors.initials: B
authors.lastname: Lavin
authors.affiliation: Department of Vascular Biology, BHF Centre of Research Excellence, Cardiovascular Division, King's College London, London, UK.
authors.forename: Alessio
authors.initials: A
authors.lastname: Alfieri
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, BHF Centre of Research Excellence and the Wellcome Trust/EPSRC Medical Engineering Centre, King's College London, London, UK.
authors.forename: Marcelo E
authors.initials: ME
authors.lastname: Andia
authors.affiliation: Division of Imaging Sciences and Biomedical Engineering, BHF Centre of Research Excellence and the Wellcome Trust/EPSRC Medical Engineering Centre, King's College London, London, UK.
authors.forename: Rene M
authors.initials: RM
authors.lastname: Botnar
authors.affiliation: Department of Clinical Pharmacology, BHF Centre of Research Excellence, Cardiovascular Division, King's College London, London, UK.
authors.forename: Albert
authors.initials: A
authors.lastname: Ferro
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000378:metabolism*; D000075388:Netrin-1; D020033:Protein Isoforms / Q000096:biosynthesis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D006657:Histones; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D001241:Aspirin
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