Oncotarget

Research Papers:

The effect of aspirin on circulating netrin-1 levels in humans is dependent on the inflammatory status of the vascular endothelium

Kerry Layne, Timothy Goodman, Albert Ferro and Gabriella Passacquale _

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Oncotarget. 2017; 8:86548-86555. https://doi.org/10.18632/oncotarget.21240

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Abstract

Kerry Layne1, Timothy Goodman1, Albert Ferro1 and Gabriella Passacquale1

1Department of Clinical Pharmacology, BHF Centre of Research Excellence, Cardiovascular Division, King’s College London, London, UK

Correspondence to:

Gabriella Passacquale, email: [email protected]

Keywords: netrin-1, endothelium, immunisation, inflammation, cyclo-oxygenase

Received: May 10, 2017     Accepted: August 07, 2017     Published: September 23, 2017

ABSTRACT

In atherosclerotic animal models, the cyclo-oxygenase (COX)-inhibitor aspirin counteracts downregulation of endothelial-derived netrin-1, thus reducing arterial inflammation. We here explored the effect of aspirin on netrin-1 in healthy subjects undergoing influenza immunisation, which is an established experimental model of inflammation-related endothelial dysfunction.

Our data showed that netrin-1 undergoes reduction (-29.25% from baseline; p=0.0017) in the presence of endothelial activation (VCAM-1 rose by 9.98% 2-days post-vaccination; p=0.0022). Aspirin counteracted vaccine-induced endothelial activation and reduction of netrin-1 in a dose-dependent manner (-3.06% and -17.03% from baseline at a dose of 300mg and 75mg respectively; p=0.0465 and p>0.05 vs untreated). Clopidogrel, which was used as a comparator due to its similar anti-platelet activity, also reduced endothelial activation but, unlike aspirin, enhanced netrin-1 levels (+20.96% from baseline; p=0.0033 vs untreated). A correlation analysis incorporating cytokines, hs-CRP, VCAM-1, TXB2 and PGE2, showed that changes in netrin-1 were directly related to PGE2 variations only (r=0.6103; p=0.0002). In a separate population of 40 healthy unimmunised volunteers, 28-day treatment with aspirin 300mg reduced netrin-1 (-18.76% from baseline; p=0.0012) without affecting endothelial markers or hs-CRP; as expected, aspirin suppressed TXB2 and PGE2. Netrin-1 and PGE2 levels were directly related (r=0.358; p=0.0015), but other parameters including TXB2, hs-CRP and endothelial markers, were not.

In conclusion, aspirin counteracts downregulation of netrin-1 following endothelial dysfunction due to its anti-inflammatory effect on the activated endothelium. However, inhibition of COX-dependent prostanoids negatively modulates netrin-1 synthesis in healthy subjects, and this could give rise to aspirin-dependent reduction in netrin-1 under steady state conditions.


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