title: Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice.
abstract: Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.
authors.affiliation: Division of Cardiology, Department of Medicine, Foundation for Medical Research, University Hospital, Faculty of Medicine, 1211 Geneva, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.forename: Niels R
authors.initials: NR
authors.lastname: Veillard
authors.forename: Claire
authors.initials: C
authors.lastname: Arnaud
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Christian
authors.initials: C
authors.lastname: Staub
authors.forename: Meliha
authors.initials: M
authors.lastname: Karsak
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Frossard
authors.forename: François
authors.initials: F
authors.lastname: Mach
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D013759:Dronabinol / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics; D015996:Survival Rate; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D013759:Dronabinol; D007371:Interferon-gamma