Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice.
OBJECTIVE
The objective of this study was to determine whether the potent selective cannabinoid receptor-1 antagonist rimonabant has antiatherosclerotic properties.


RESULTS
Rimonabant (50 mg/kg/d in the diet) significantly reduced food intake (from 3.35+/-.04 to 2.80+/-0.03 g/d), weight gain (from 14.6+/-0.7 g to -0.6+/-0.3 g), serum total cholesterol (from 8.39+/-0.54 to 5.32+/-0.18 g/L), and atherosclerotic lesion development in the aorta (from 1.7+/-0.22 to 0.21+/-0.037 mm(2)) and aortic sinus (from 101,000+/-7800 to 27,000+/-2900 microm(2)) of LDLR(-/-) mice fed a Western-type diet for 3 months. Rimonabant also reduced plasma levels of the proinflammatory cytokines MCP-1 and IL12 by 85% (P<0.05) and 76% (P<0.05), respectively. Pair-fed animals had reduced weight gain (6.2+/-0.6 g gain), but developed atherosclerotic lesions which were as large as those of untreated animals, showing that the antiatherosclerotic effect of rimonabant is not related to reduced food intake. Interestingly, rimonabant at a lower dose (30 mg/kg/d in the diet) reduced atherosclerosis development in the aortic sinus (from 121,000+/-20,000 to 62,000+/-11,000 microm(2), 49% reduction, P<0.05), without affecting serum total cholesterol (7.8+/-0.7 g/L versus 8.1+/-1.3 g/L in the control group). Rimonabant decreased lipopolysaccharide (LPS)- and IL1beta-induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollate-induced recruitment of macrophages in vivo (10 mg/kg, p.o. bolus).


CONCLUSIONS
These results show that rimonabant has antiatherosclerotic effects in LDLR(-/-) mice. These effects are partly unrelated to serum cholesterol modulation and could be related to an antiinflammatory effect.
Sanofi-Aventis Recherche & Développement, Toulouse, France.
Frédérique
F
Dol-Gleizes
Réjane
R
Paumelle
Virgile
V
Visentin
Anne-Marie
AM
Marés
Perrine
P
Desitter
Nathalie
N
Hennuyer
Andries
A
Gilde
Bart
B
Staels
Paul
P
Schaeffer
Françoise
F
Bono
D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D002149:Energy Intake / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000517:prevention & control; D018664:Interleukin-12 / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D011973:Receptors, LDL / Q000172:deficiency*; D000077285:Rimonabant
D002186:Cannabinoids; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D011973:Receptors, LDL; D018664:Interleukin-12; D002784:Cholesterol; D000077285:Rimonabant