Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice.

Détails

ID Serval
serval:BIB_AF5B98C9CD38
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice.
Périodique
Arteriosclerosis, Thrombosis, and Vascular Biology
Auteur(s)
Lenglet S., Thomas A., Soehnlein O., Montecucco F., Burger F., Pelli G., Galan K., Cravatt B., Staub C., Steffens S.
ISSN
1524-4636 (Electronic)
ISSN-L
1079-5642
Statut éditorial
Publié
Date de publication
2013
Volume
33
Numéro
2
Pages
215-223
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Résumé
OBJECTIVE: Endocannabinoid levels are elevated in human and mouse atherosclerosis, but their causal role is not well understood. Therefore, we studied the involvement of fatty acid amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in atherosclerotic plaque vulnerability.
METHODS AND RESULTS: We assessed atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) and ApoE(-/-)FAAH(-/-) mice. Before and after 5, 10, and 15 weeks on high-cholesterol diet, we analyzed weight, serum cholesterol, and endocannabinoid levels, and atherosclerotic lesions in thoracoabdominal aortas and aortic sinuses. Serum levels of FAAH substrates anandamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were 1.4- to 2-fold higher in case of FAAH deficiency. ApoE(-/-)FAAH(-/-) mice had smaller plaques with significantly lower content of smooth muscle cells, increased matrix metalloproteinase-9 expression, and neutrophil content. Circulating and bone marrow neutrophil counts were comparable between both genotypes, whereas CXC ligand1 levels were locally elevated in aortas of FAAH-deficient mice. We observed enhanced recruitment of neutrophils, but not monocytes, to large arteries of ApoE(-/-) mice treated with FAAH inhibitor URB597. Spleens of ApoE(-/-)FAAH(-/-) mice had reduced CD4+FoxP3+regulatory T-cell content, and in vitro stimulation of splenocytes revealed significantly elevated interferon-γ and tumor necrosis factor-α production in case of FAAH deficiency.
CONCLUSIONS: Increased anandamide and related FAAH substrate levels are associated with the development of smaller atherosclerotic plaques with high neutrophil content, accompanied by an increased proinflammatory immune response.
Mots-clé
Amidohydrolases/antagonists & inhibitors, Amidohydrolases/deficiency, Animals, Aorta/drug effects, Aorta/enzymology, Aortic Diseases/enzymology, Aortic Diseases/genetics, Apolipoproteins E/deficiency, Apolipoproteins E/genetics, Arachidonic Acids/blood, Atherosclerosis/enzymology, Atherosclerosis/genetics, Benzamides/pharmacology, Carbamates/pharmacology, Cells, Cultured, Chemokine CXCL1/metabolism, Cholesterol/blood, Disease Models, Animal, Endocannabinoids/blood, Enzyme Inhibitors/pharmacology, Ethanolamines/blood, Genotype, Inflammation Mediators/metabolism, Interferon-gamma/metabolism, Matrix Metalloproteinase 9/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular/immunology, Muscle, Smooth, Vascular/pathology, Neutrophil Infiltration/drug effects, Neutrophils/drug effects, Neutrophils/immunology, Oleic Acids/blood, Palmitic Acids/blood, Phenotype, Plaque, Atherosclerotic, Polyunsaturated Alkamides/blood, Spleen/immunology, T-Lymphocytes, Regulatory/immunology, Time Factors, Tumor Necrosis Factor-alpha/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
21/01/2015 18:06
Dernière modification de la notice
08/05/2019 23:46
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