Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice.
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.
Steffens
Sabine
S
Division of Cardiology, Department of Medicine, Foundation for Medical Research, University Hospital, Faculty of Medicine, 1211 Geneva, Switzerland.
Veillard
Niels R
NR
Arnaud
Claire
C
Pelli
Graziano
G
Burger
Fabienne
F
Staub
Christian
C
Karsak
Meliha
M
Zimmer
Andreas
A
Frossard
Jean-Louis
JL
Mach
François
F
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
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