Impaired Production and Diurnal Regulation of Vascular RvD_{n-3 DPA} Increase Systemic Inflammation and Cardiovascular Disease.

Abstract

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. Herein, we investigated the diurnal regulation of specialized proresolving mediators in humans and their role in controlling peripheral blood leukocyte and platelet activation. 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 B₂ concentrations, and aortic lesions. 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.