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.

Abstract-Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a chemokine pathway in vivo with the CC chemokine antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major chemokines and chemokine receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC chemokine or its receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a chemokine receptor antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease. A therosclerosis is an inflammatory disease characterized by arterial lesions containing cholesterol, immune infiltrates, and fibrosis, 1-3 resulting essentially from hyperlipidemia, hypertension, smoking, and diabetes. 4 These cardiovascular risk factors cause endothelial dysfunction, which triggers the migration of leukocytes, mainly of monocyte/ macrophage and T lymphocyte type, within the vessel wall intima area. Proinflammatory factors, such as cytokines and chemokines, released from endothelial cells (ECs), macrophages, or T cells, cause proliferation and migration of smooth muscle cells (SMCs) from the media to the intima, as well as recruitment of new immunoinflammatory cells. Within the intima, SMCs secrete extracellular matrix components, leading to the accumulation of collagen and proteoglycans, key factors implicated in plaque stability. Conversely, the secretion of matrix metalloproteinases by vascular and inflammatory cells degrades matrix components, such as collagen, gelatin, or elastin within atherosclerotic lesions.Chemokines (chemotactic cytokines) belong to a large superfamily of low molecular weight proteins with a highly homologous 3-dimensional structure, which are divided into four groups based on the configuration of the first two cysteines. 5,6 Chemokines are known to induce leukocyte migration, growth, and activation through 7 transmembrane heptahelical, G protein-coupled cell-surface receptors on target cells and regulate leukocyte trafficking during inflammation. The chemokine CCL5/RANTES (Regulated on Activated Normal T-Cell Expressed and Secreted) is a soluble chemokine of 7.8 kDa secreted by many different cell types, such as ECs, SMCs, activated T cells, macrophages, and platelets. 7,8 RANTES interacts with the chemokine receptors CCR1, CCR3, and CCR5, and has been implicated i...

These results suggest that anti-ApoA-1 IgG might be associated with increased atherosclerotic plaque vulnerability in humans and mice.

Objective-Chemokines and their receptors are crucially involved in the development of atherosclerotic lesions by directing monocyte and T cell recruitment. The CC-chemokine receptors 1 (CCR1) and 5 (CCR5) expressed on these cells bind chemokines implicated in atherosclerosis, namely CCL5/RANTES. Although general blockade of CCL5 receptors reduces atherosclerosis, specific roles of CCR1 and CCR5 have not been unequivocally determined. Methods and Results-We provide two independent lines of investigation to dissect the effects of Ccr1 and Ccr5 deletion in apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice in a collaboration between Aachen/Germany and Geneva/Switzerland. Different strains of ApoE Ϫ/Ϫ Ccr5 Ϫ/Ϫ mice, ApoE Ϫ/Ϫ Ccr1 Ϫ/Ϫ mice or respective littermates, were fed a high-fat diet for 10 to 12 weeks. Plaque areas were quantified in the aortic roots and thoracoabdominal aortas. Concordantly, both laboratories found that lesion formation was reduced in ApoE Ϫ/Ϫ Ccr5 Ϫ/Ϫ mice. Plaque quality and immune cells were assessed by immunohistochemistry or mRNA analysis. Whereas lesional macrophage content, aortic CD4, and Th1-related Tim3 expression were reduced, smooth muscle cell (SMC) content and expression of interleukin-10 in plaques, lesional SMCs, and splenocytes were elevated. Protection against lesion formation by Ccr5 deficiency was sustained over 22 weeks of high-fat diet or over 26 weeks of chow diet. Conversely, plaque area, T cell, and interferon-␥ content were increased in ApoE Ϫ/Ϫ Ccr1 Ϫ/Ϫ mice. Conclusion-Genetic deletion of Ccr5 but not Ccr1 in ApoEϪ/Ϫ mice protects from diet-induced atherosclerosis, associated with a more stable plaque phenotype, reduced mononuclear cell infiltration, Th1-type immune responses, and increased interleukin-10 expression. This corroborates CCR5 as a promising therapeutic target. (Arterioscler Thromb Vasc Biol.

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