Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 38, Issue 11, Pages 2562-2575Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.118.311185
Keywords
atherosclerosis; cholesterol; fatty acids; inflammation; macrophages
Categories
Funding
- Academy of Finland [274852, 286284]
- Finnish Foundation for Cardiovascular Research
- Paavo Nurmi Foundation
- Deutsche Forschungsgemeinschaft [STE-1053/3-1, SFB1123 TP A1]
- Else Kroener Fresenius Foundation [2013_ A114]
- German Centre for Cardiovascular Research [DZHK MHA VD1.2, DZHK B18-015-SE]
- European Research Council ERC [AdG 692511]
- Alexander von Humboldt Foundation
- Tampere University Hospital [9M048, 9N035]
- Emil Aaltonen Foundation
- Pirkanmaa Regional Fund of the Finnish Cultural Foundation
- Research Foundation of Orion Corporation
- Jenny and Antti Wihuri Foundation
- Yrjo Jahnsson Foundation
- European Union [201668]
- EU Horizon 2020 [755320]
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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- (peroxisome proliferator-activated receptors ) 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.
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