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

Details

Serval ID
serval:BIB_AF5B98C9CD38
Type
Article: article from journal or magazin.
Collection
Publications
Title
Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice.
Journal
Arteriosclerosis, Thrombosis, and Vascular Biology
Author(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
Publication state
Published
Issued date
2013
Volume
33
Number
2
Pages
215-223
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
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.
Keywords
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
Yes
Create date
21/01/2015 17:06
Last modification date
20/08/2019 15:18
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