RT Journal Article
T1 Aspirin‐induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin‐1 thus inhibiting monocyte vascular infiltration
A1 Passacquale, Gabriella
A1 Phinikaridou, Alkystis
A1 Warboys, Christina
A1 Cooper, Margaret
A1 Lavín Plaza, Begoña
A1 Alfieri, Alessio
A1 Andia, Marcelo
A1 Botnar, Rene
A1 Ferro, Albert
AB 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.
PB Wiley
SN 0007-1188
YR 2015
FD 2015
LK https://hdl.handle.net/20.500.14352/99058
UL https://hdl.handle.net/20.500.14352/99058
LA eng
NO Passacquale, Gabriella, et al. «Aspirin‐induced Histone Acetylation in Endothelial Cells Enhances Synthesis of the Secreted Isoform of Netrin‐1 Thus Inhibiting Monocyte Vascular Infiltration». British Journal of Pharmacology, vol. 172, n.o 14, julio de 2015, pp. 3548-64. https://doi.org/10.1111/bph.13144.
DS Docta Complutense
RD 11 abr 2025