Impaired Production and Diurnal Regulation of Vascular RvD Increase 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 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) 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 and markers of platelet, monocyte, and neutrophil activation, including CD63 and CD11b. Incubation of RvD with peripheral blood from healthy volunteers and patients with cardiovascular disease significantly and dose-dependently decreased platelet and leukocyte activation. Furthermore, administration of RvD5 to ApoE (apolipoprotein E deficient) mice significantly reduced platelet-leukocyte aggregates, vascular thromboxane B concentrations, and aortic lesions.

CONCLUSIONS

These results demonstrate that peripheral blood RvD are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease.