title: Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice.
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.
  
  
  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.
authors.affiliation: Division of Cardiology, Foundation for Medical Researches, 64 Ave Roseraie, 1211 Geneva, Switzerland. sabine.steffens@unige.ch
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lenglet
authors.forename: Aurélien
authors.initials: A
authors.lastname: Thomas
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Katia
authors.initials: K
authors.lastname: Galan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cravatt
authors.forename: Christian
authors.initials: C
authors.lastname: Staub
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
mesh_terms: D000577:Amides; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001095:Arachidonic Acids / Q000097:blood; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000097:blood; D005838:Genotype; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D009829:Oleic Acids / Q000097:blood; D010169:Palmitic Acids / Q000097:blood; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D053284:Polyunsaturated Alkamides / Q000097:blood; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000577:Amides; D000581:Amidohydrolases; D001057:Apolipoproteins E; D001095:Arachidonic Acids; D001549:Benzamides; D002219:Carbamates; D054360:Chemokine CXCL1; D002784:Cholesterol; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D020780:Matrix Metalloproteinase 9; D009829:Oleic Acids; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; D014409:Tumor Necrosis Factor-alpha; D000099252:Fatty Acid Amide Hydrolases; C475895:Cxcl1 protein, mouse; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C488250:oleoylethanolamide; C005958:palmidrol; C501830:Mmp9 protein, mouse; C078814:anandamide