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Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice

A Corrigendum to this article was published on 26 May 2005

Abstract

Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries1. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions2 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 cells2,3) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-γ secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis1, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist4. 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.

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Figure 1: The cannabinoid receptor CB2 is expressed in human and mouse atherosclerotic plaques.
Figure 2: The cannabinoid receptor CB2 is expressed on macrophages and T lymphocytes within atherosclerotic plaques of ApoE-/- mice.
Figure 3: Reduced atherosclerotic plaque development and macrophage content in THC-treated ApoE-/- mice.
Figure 4: THC reduces proliferative responses and inhibits TH1 polarization.
Figure 5: THC reduces migration capacity and CCR2 expression in vitro.

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Acknowledgements

This work was supported by grants from the Swiss National Science Foundation to F.M. and J.-L.F., from the Ernst and Lucie Schmidheiny Foundation (Geneva) to F.M., and from the Foundation for Medical Research (France) to C.A. The authors of this manuscript belong to the European Vascular Genomics Network (http://www.evgn.org), a Network of Excellence supported by the European Community's sixth Framework Programme for Research, Priority 1. We would like to thank M. Kosco-Vilbois for helpful discussion in preparing the manuscript, and M.-L. Bochaton-Piallat (Pathology Department) for technical advice.

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Correspondence to François Mach.

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Steffens, S., Veillard, N., Arnaud, C. et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434, 782–786 (2005). https://doi.org/10.1038/nature03389

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