Impaired Production and Diurnal Regulation of Vascular RvDn-3 DPA Increases Systemic Inflammation and Cardiovascular Disease
Rationale: Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized pro-resolving mediators (SPM) that terminate inflammation without interfering with the immune response. Little is known on their diurnal regulation.
Objective: Herein we investigated the diurnal regulation of SPM 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 (RvDn-3 DPA) were regulated in a diurnal manner. The production and diurnal 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 RvDn-3 DPA and markers of platelet, monocyte and neutrophil activation including CD63 and CD11b. Incubation of RvDn-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 RvD5n-3 DPA to apolipoprotein E deficient mice significantly reduced platelet-leukocyte aggregates, vascular thromboxane B2 concentrations and aortic lesions.
Conclusions: These results demonstrate that peripheral blood RvDn-3 DPA are diurnally regulated in humans and dysregulation in the production of these mediators may lead to cardiovascular disease.
- lipid mediators
- vascular biology
- systemic inflammation
- polymorphonuclear neutrophils activation
- Received November 29, 2017.
- Revision received January 31, 2018.
- Accepted February 2, 2018.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License (http://creative commons.org/licenses/by-nc/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.