Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice
SABINE STEFFENS(1), NIELS R. VEILLARD(1)*, CLAIRE ARNAUD(1)*, GRAZIANO PELLI(1), FABIENNE BURGER(1), CHRISTIAN STAUB(3), ANDREAS ZIMMER(4), JEAN-LOUIS FROSSARD(2) & FRANÇOIS MACH(1)
(1) Division of Cardiology, Department of Medicine, Foundation for Medical Research, University Hospital, Faculty of Medicine, 1211 Geneva, Switzerland
(2) Division of Gastroenterology, University Hospital, Faculty of Medicine, 1211 Geneva, Switzerland
(3) Institute of Legal Medicine, University Hospital, Faculty of Medicine, 1211 Geneva, Switzerland
(4) Laboratory for Molecular Neurobiology, Department of Psychiatry, University of Bonn, 53105 Bonn, Germany
* These authors contributed equally to this work
Correspondence and requests for materials should be addressed to F.M. (Francois.Mach@medecine.unige.ch).
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- 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.
