Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation.

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.

• Authors: Petteri Rinne, Raquel Guillamat-Prats, Martina Rami, Laura Bindila, Larisa Ring, Leo-Pekka Lyytikäinen, Emma Raitoharju, Niku Oksala, Terho Lehtimäki, Christian Weber, Emiel P C van der Vorst, Sabine Steffens
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 38 Issue 11 Pg. 2562-2575 (11 2018) ISSN: 1524-4636 [Electronic] United States
• PMID: 30354245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Anti-Inflammatory Agents
• Ethanolamines
• GPR55 protein, mouse
• MAS1 protein, human
• Palmitic Acids
• Proto-Oncogene Mas
• Receptors, Cannabinoid
• palmidrol
• Mertk protein, mouse
• c-Mer Tyrosine Kinase
• N-acylphosphatidylethanolamine phospholipase D, mouse
• Phospholipase D
• NAPEPLD protein, human

Topics

• Amides
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Aorta (drug effects, metabolism, pathology)
• Aortic Diseases (genetics, metabolism, pathology, prevention & control)
• Atherosclerosis (genetics, metabolism, pathology, prevention & control)
• Cell Line
• Disease Models, Animal
• Ethanolamines (pharmacology)
• Female
• Humans
• Macrophages (drug effects, metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• Palmitic Acids (pharmacology)
• Phagocytosis (drug effects)
• Phenotype
• Phospholipase D (metabolism)
• Plaque, Atherosclerotic
• Proto-Oncogene Mas
• Rats
• Receptors, Cannabinoid (genetics, metabolism)
• Time Factors
• c-Mer Tyrosine Kinase (metabolism)