Romain A Colas1, Patricia R Souza1, Mary E Walker1, Maudrian Burton1, Zbigniew Zasłona1, Annie M Curtis1, Raquel M Marques1, Jesmond Dalli2. 1. From the Lipid Mediator Unit, William Harvey Research Institute (R.A.C., P.R.S., M.E.W., R.M.M., J.D.) NIHR Cardiovascular Biomedical Research Unit at Barts (M.B.), and the Centre for Inflammation and Therapeutic Innovation (J.D.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland (Z.Z.); and Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin (A.M.C.). 2. From the Lipid Mediator Unit, William Harvey Research Institute (R.A.C., P.R.S., M.E.W., R.M.M., J.D.) NIHR Cardiovascular Biomedical Research Unit at Barts (M.B.), and the Centre for Inflammation and Therapeutic Innovation (J.D.), Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland (Z.Z.); and Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin (A.M.C.). j.dalli@qmul.ac.uk.
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.
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.
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