Open AccessImpaired Production and Diurnal Regulation of Vascular RvD n-3 DPA Increase Systemic Inflammation and Cardiovascular Disease
Author(s) -
Romain A. Colas,
Patricia R. Souza,
Mary E. Walker,
Maudrian Burton,
Zbigniew Zasłona,
Anne M. Curtis,
Raquel M. Marques,
Jesmond Dalli
Publication year - 2018
Publication title -
circulation research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.899
H-Index - 336
eISSN - 1524-4571
pISSN - 0009-7330
DOI - 10.1161/circresaha.117.312472
Subject(s) - inflammation , platelet activation , medicine , endocrinology , platelet , systemic inflammation , p2y12 , immune system , lipid signaling , immunology , platelet aggregation
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 (RvDn-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 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 ApoE−/− (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.