Journal
CIRCULATION RESEARCH
Volume 122, Issue 6, Pages 855-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.117.312472
Keywords
adenosine; eicosanoids; lipoxygenase; monocyte; neutrophils; platelets
Funding
- Sir Henry Dale Fellowship - Wellcome Trust [107613/Z/15/Z]
- Sir Henry Dale Fellowship - Royal Society [107613/Z/15/Z]
- European Research Council under the European Union's Horizon research and innovation program [677542]
- Barts Charity [MGU0343]
- Medical Research Council Advance Course Masters [MR/J015741/1]
- Science Foundation Ireland Starting Investigator Research Grant [13/SIRG/2130]
- Wellcome Trust grant [101604/Z/13/Z]
- National Institute for Health Research
- Wellcome Trust [101604/Z/13/Z] Funding Source: Wellcome Trust
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Rationale: Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized proresolving mediators that terminate inflammation without interfering with the immune response. Objective: Herein, we investigated the diurnal regulation of specialized proresolving mediators in humans and their role in controlling peripheral blood leukocyte and platelet activation. Methods and Results: Using lipid mediator profiling and healthy volunteers, we found that plasma concentrations of n-3 docosapentaenoic acid-derived D-series resolvins (RvD(n-3) (DPA)) were regulated in a diurnal manner. The production and regulation of these mediators was markedly altered in patients at risk of myocardial infarct. These changes were associated with decreased 5-lipoxygenase expression and activity, as well as increased systemic adenosine concentrations. We also found a significant negative correlation between plasma RvD(n-3) (DPA) and markers of platelet, monocyte, and neutrophil activation, including CD63 and CD11b. Incubation of RvD(n-3) (DPA) with peripheral blood from healthy volunteers and patients with cardiovascular disease significantly and dose-dependently decreased platelet and leukocyte activation. Furthermore, administration of RvD5(n-3) (DPA) to ApoE(-/-) (apolipoprotein E deficient) mice significantly reduced platelet-leukocyte aggregates, vascular thromboxane B-2 concentrations, and aortic lesions. Conclusions: These results demonstrate that peripheral blood RvD(n-3) (DPA) are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease.
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