Treatment With a Marine Oil Supplement Alters Lipid Mediators and Leukocyte Phenotype in Healthy Patients and Those With Peripheral Artery Disease

Melinda S Schaller, Mian Chen, Romain A Colas, Thomas A Sorrentino, Ann A Lazar, S Marlene Grenon, Jesmond Dalli, Michael S Conte, Melinda S Schaller, Mian Chen, Romain A Colas, Thomas A Sorrentino, Ann A Lazar, S Marlene Grenon, Jesmond Dalli, Michael S Conte

Abstract

Background Peripheral artery disease (PAD) is an advanced form of atherosclerosis characterized by chronic inflammation. Resolution of inflammation is a highly coordinated process driven by specialized pro-resolving lipid mediators endogenously derived from omega-3 fatty acids. We investigated the impact of a short-course, oral, enriched marine oil supplement on leukocyte phenotype and biochemical mediators in patients with symptomatic PAD and healthy volunteers. Methods and Results This was a prospective, open-label study of 5-day oral administration of an enriched marine oil supplement, assessing 3 escalating doses in 10 healthy volunteers and 10 patients with PAD. Over the course of the study, there was a significant increase in the plasma level of several lipid mediator families, total specialized pro-resolving lipid mediators, and specialized pro-resolving lipid mediator:prostaglandin ratio. Supplementation was associated with an increase in phagocytic activity of peripheral blood monocytes and neutrophils. Circulating monocyte phenotyping demonstrated reduced expression of multiple proinflammatory markers (cluster of differentiation 18, 163, 54, and 36, and chemokine receptor 2). Similarly, transcriptional profiling of monocyte-derived macrophages displayed polarization toward a reparative phenotype postsupplementation. The most notable cellular and biochemical changes over the study occurred in patients with PAD. There were strong correlations between integrated biochemical measures of lipid mediators (specialized pro-resolving lipid mediators:prostaglandin ratio) and phenotypic changes in circulating leukocytes in both healthy individuals and patients with PAD. Conclusions These data suggest that short-term enriched marine oil supplementation dramatically remodels downstream lipid mediator pathways and induces a less inflammatory and more pro-resolution phenotype in circulating leukocytes and monocyte-derived macrophages. Further studies are required to determine the potential clinical relevance of these findings in patients with PAD. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02719665.

Keywords: fatty acids; inflammation; lipid metabolites; peripheral artery disease; vascular disease.

Conflict of interest statement

Conte is co‐inventor on patents (US Patent and Trademark Office numbers 9,463,177 and 10,111,847) assigned to Regents of the University of California and Brigham and Women's Hospital and co‐founder of VasaRx, and reports research support from Metagenics Inc. The remaining authors have no disclosures to report.

Figures

Figure 1
Figure 1
Schematic of study design. SPM indicates specialized pro‐resolving lipid mediator; and V, visit number.
Figure 2
Figure 2
Lipid mediator (LM) profiles were investigated in (A through C) healthy volunteers and (D through F) patients with peripheral artery disease (PAD) presupplementation (visit [V] 1, V3, and V5) and postsupplementation (V2, V4, and V6). Results were interrogated using partial least squares discriminant analysis following auto‐scaling (mean‐centered and divided by the SD of each variable). The colored area represents the 95% CI. (Top panels) Score plots and (bottom panels) plots displaying the LM with the 10 highest variable importance in projection (VIP) scores from component 1. Results are representative of n=10 for healthy volunteers and, n=8 to 10 for patients with PAD V1 to V2, n=10 for patients with PAD V3 to V6.
Figure 3
Figure 3
Dose‐dependent changes for omega‐3 (n‐3) fatty acids (docosahexanoic acid [DHA], n‐3 docosapentaenoic acid [DPA], eicosapentaenoic acid [EPA]), arachidonic acid (AA), and total specialized pro‐resolving lipid mediators (SPMs) for healthy participants (A) and patients with peripheral artery disease (B). V indicates visit number.
Figure 4
Figure 4
Illustration of the changes in lipid mediator biochemistry and leukocyte (monocyte and monocyte‐derived macrophage) phenotype in patients with peripheral artery disease with marine oil supplementation. The balance shifts from inflammation towards resolution. CCR2 indicates chemokine receptor 2; CD, cluster of differentiation; DHA, docosahexanoic acid; DPA, docosapentaenoic acid; EPA, eicosapentaenoic acid; M1, type 1 macrophage; M2, type 2 macrophage; n‐3, omega‐3; and SPM, specialized pro‐resolving lipid mediators.

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