Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation. Issue 11 (November 2018)

• Record Type: Journal Article
• Authors: Rinne, Petteri; Guillamat-Prats, Raquel; Rami, Martina; Bindila, Laura; Ring, Larisa; Lyytikäinen, Leo-Pekka; Raitoharju, Emma; Oksala, Niku; Lehtimäki, Terho; Weber, Christian; van der Vorst, Emiel P.C.; Steffens, Sabine
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 38:Issue 11(2018)
• Publication Date: 2018-11
• Subjects: atherosclerosis -- cholesterol -- fatty acids -- inflammation -- macrophages; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.118.311185
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Objective—: Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N -acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR-α (peroxisome proliferator-activated receptors α) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored. Approach and Results—: First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce N -acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability. N -acyl phosphatidylethanolamine phospholipase D expression was progressively downregulated in the aorta of apolipoprotein E deficient (ApoE −/− ) mice during atherogenesis. N -acyl phosphatidylethanolamine phospholipase D mRNA levels were also downregulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second, ApoE − /− mice were fed a high-fat diet for 4 or 16 weeks and treated with either vehicle or palmitoylethanolamide (3 mg/kg per day, 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downregulation of M1-type macrophage markers. Mechanistically, we found that palmitoylethanolamide, by activating GPR55, increases the expression of the phagocytosis receptor MerTK (proto-oncogene tyrosine-protein kinase MER) and enhances macrophage efferocytosis, indicative of proresolving properties. Conclusions—: The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation. Abstract : Supplemental Digital Content is available in the text.