title: Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis.
abstract: In this study we analysed the possible modulation of endocannabinoids and related molecules during atherosclerosis development in mice. Wild-type and apolipoprotein E knockout (ApoE(-/-)) mice were fed either normal chow or high-cholesterol diet for 8-12 weeks, and tissue endocannabinoid levels were measured by liquid chromatography-mass spectrometry. We found increased levels of 2-AG in aortas and visceral adipose tissue (VAT) of ApoE(-/-) mice fed on high-cholesterol diet for 12 weeks as compared to ApoE(-/-) mice fed on normal chow or wild-type mice fed on cholesterol. No significant difference in 2-AG levels was observed after 8 weeks of diet, and no changes in anandamide levels were found in any group. The levels of the anandamide-related mediators with anti-inflammatory or anti-lipogenic properties, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), decreased or increased only in VAT or in both tissues, respectively. Endocannabinoid- and OEA/PEA-degrading enzymes were expressed by macrophages within atherosclerotic lesions. In vitro, 2-AG and OEA-induced monocyte migration at 0.3-1microM, which corresponds to the levels observed in aortas. PEA 1microM also induced monocyte migration but counteracted the effect of 2-AG, whereas OEA enhanced it. Enhanced 2-AG levels in advanced atherosclerotic lesions may trigger the inflammatory process by recruiting more inflammatory cells and inducing extracellular matrix degradation via CB(2) receptors, and this possibility was supported in vitro but not in vivo by experiments with the CB(2) antagonist, SR144528.
authors.affiliation: Department of Internal Medicine, University Hospital, Geneva, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Isabel
authors.initials: I
authors.lastname: Matias
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lenglet
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000577:Amides; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D001892:Camphanes / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D063388:Endocannabinoids; D004983:Ethanolamines; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009829:Oleic Acids / Q000378:metabolism; D010169:Palmitic Acids / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism
chemical_list: D000577:Amides; D001057:Apolipoproteins E; D001892:Camphanes; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; D009829:Oleic Acids; D010169:Palmitic Acids; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C488250:oleoylethanolamide; C005958:palmidrol; D002784:Cholesterol