Aspirin‐induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin‐1 thus inhibiting monocyte vascular infiltration

Abstract

Background and PurposeThere 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 ApproachNetrin-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 ResultsTNF-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 ImplicationsAspirin 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.

Low-intensity pulsed ultrasound (LIPUS) prevents periprosthetic inflammatory loosening through FBXL2-TRAF6 ubiquitination pathway

“…Netrin-1 is a neuroimmune guidance cue. It can inhibit the migration of macrophages, which means that it is an inflammatory factor3536. This can explain the reduced transwell rate of RAW 264.7 cell by polyethylene debris in our study.…”

Gadolinium deposition and the potential for toxicological sequelae – A literature review of issues surrounding gadolinium‐based contrast agents

“…Human monocyte‐derived macrophages that were incubated with the linear agent, gadodiamide (50 mmol l –1 ), showed increased gene expression, as well as increased ‘nuclear factor kappa‐light‐chain‐enhancer of activated B cells’ activity . This is a transcription factor that plays a critical role in the induction of the inflammatory response and chemokine production, and also regulates expression of the cyclo‐oxygenase‐2 enzyme . An additional study where human dermal fibroblasts were incubated with GBCA‐treated monocyte culture supernatants showed a significant increase in production of types I and III collagen, fibronectin and α‐smooth muscle actin expression in normal dermal fibroblasts .…”

Impact of aspirin use on morbidity and mortality in massively transfused cardiac surgery patients: a propensity score matched cohort study

“…We hypothesized that aspirin might be beneficial in massively transfused patients because it has been shown to induce nitric oxide release from endothelial cells and may help to preserve normal endothelial function during transfusion [26]. Aspirin also stimulates anti-inflammatory effects in endothelial cells via histone acetylation, which can decrease monocyte infiltration [27]. Finally, in an animal model of TRALI, aspirin was shown to mitigate lung injury by reducing platelet neutrophil aggregation in the pulmonary circulation [10].…”