BACKGROUND AND PURPOSE: There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, since 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 TNFα either in the presence or absence of aspirin treatment. In vivo experiments were conducted in ApoE(-/-) mice fed a high-fat diet (HFD), receiving either aspirin or clopidogrel.
KEY RESULTS: TNFα-induced NF-êB activation up-regulated the nuclear isoform of netrin-1, whilst simultaneously reducing secreted netrin-1. Down-regulation of the secreted isoform compromised the chemorepellent action of the endothelium against monocyte chemotaxis. Aspirin counteracted TNFα-mediated effects on netrin-1 synthesis by endothelial cells through cyclooxygenase-dependent inhibition of NF-êB 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, and this was paralleled 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 monocyte arterial accumulation.