Impaired Production and Diurnal Regulation of Vascular RvDn-3 DPA Increase Systemic Inflammation and Cardiovascular Disease

• Published in: Circulation research 2018-03, Vol.122 (6), p.855-863
• Main Authors: Colas, Romain A, Souza, Patricia R, Walker, Mary E, Burton, Maudrian, Zasłona, Zbigniew, Curtis, Annie M, Marques, Raquel M, Dalli, Jesmond
• Format: Article
• Language: English
• Subjects: Adenosine; Aorta; Apolipoprotein E; Arachidonate 5-lipoxygenase; Blood platelets; Cardiovascular disease; CD11b antigen; CD63 antigen; Cell activation; Diurnal; Immune response; Lipoxygenase; Monocytes; Myocardial infarction; Peripheral blood; Platelets
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.117.312472

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.