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

Circ Res. 2018 Mar 16;122(6):855-863. doi: 10.1161/CIRCRESAHA.117.312472. Epub 2018 Feb 5.

Abstract

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.

Keywords: adenosine; eicosanoids; lipoxygenase; monocyte; neutrophils; platelets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / blood
  • Animals
  • Blood Platelets / metabolism
  • Circadian Rhythm*
  • Fatty Acids, Unsaturated / blood*
  • Humans
  • Inflammation / blood
  • Leukocytes / metabolism
  • Lipoxygenase / blood
  • Mice
  • Myocardial Infarction / blood*
  • Thromboxane B2 / blood

Substances

  • Fatty Acids, Unsaturated
  • Thromboxane B2
  • Lipoxygenase
  • Adenosine
  • docosapentaenoic acid