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Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2018 Nov; Vol. 38 (11), pp. 2562-2575. - Publication Year :
- 2018
-
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 <superscript>-/-</superscript> ) 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 <superscript>-</superscript> <superscript>/-</superscript> 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.
- Subjects :
- Amides
Animals
Aorta metabolism
Aorta pathology
Aortic Diseases genetics
Aortic Diseases metabolism
Aortic Diseases pathology
Atherosclerosis genetics
Atherosclerosis metabolism
Atherosclerosis pathology
Cell Line
Disease Models, Animal
Female
Humans
Macrophages metabolism
Macrophages pathology
Mice, Inbred C57BL
Mice, Knockout, ApoE
Phenotype
Phospholipase D metabolism
Proto-Oncogene Mas
Rats
Receptors, Cannabinoid genetics
Receptors, Cannabinoid metabolism
Time Factors
c-Mer Tyrosine Kinase metabolism
Anti-Inflammatory Agents pharmacology
Aorta drug effects
Aortic Diseases prevention & control
Atherosclerosis prevention & control
Ethanolamines pharmacology
Macrophages drug effects
Palmitic Acids pharmacology
Phagocytosis drug effects
Plaque, Atherosclerotic
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 38
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 30354245
- Full Text :
- https://doi.org/10.1161/ATVBAHA.118.311185