Cannabinoid 1 receptor blockade reduces atherosclerosis with enhances reverse cholesterol transport.
OBJECTIVE
A recent clinical study using coronary intravascular ultrasound showed that rimonabant, a cannabinoid 1 (CB1) receptor antagonist, significantly reduced total atheroma volume, suggesting that CB1 receptor blockade could be beneficial in anti-atherogenic therapy. The reverse cholesterol transport (RCT) system plays important roles in atherogenesis. We investigated whether CB1 receptor blockade could modulate atherogenesis in mice.


RESULTS
Oral administration of rimonabant (8 mg/kg/day) to apolipoprotein E-deficient mice for 3 months significantly reduced the relative area of atherosclerotic lesions in the aorta (vehicle; 12.6+/-4.0% vs. rimonabant; 9.7+/-2.3, n=12 each, p<0.05) with an increase in serum adiponectin levels (15.6+/-2.3 microg/mL vs. 12.2+/-2.1, n=12 each, p<0.001), without affecting body weight or serum cholesterol levels. Rimonabant tended to increase serum high-density lipoprotein cholesterol (HDL-C) (p=0.05). The relative area of atherosclerotic lesions in the aorta correlated inversely with serum HDL-C levels (r=-0.45, n=24, p<0.05). Rimonabant upregulated the mRNA expression levels of various components of the RCT system on THP-1 cell-derived macrophages (scavenger receptor B1: 1.15+/-0.12 fold, n=6; p<0.05, ATP-binding cassette [ABC] transporter G1: 1.23+/-0.11 fold, n=6; p<0.01), but not ABCA1 (1.13+/-0.20 fold, n=6; p=0.13).


CONCLUSIONS
CB1 receptor blockade reduced atherosclerosis in apoE-deficient mice through an increase in serum adiponectin levels and activation of the RCT system. CB1 receptor blockade may be therapeutically beneficial for atherogenesis by increasing the serum adiponectin level and enhancing of the RCT system.
Sugamura
Koichi
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Sugiyama
Seigo
S
Fujiwara
Yukio
Y
Matsubara
Junichi
J
Akiyama
Eiichi
E
Maeda
Hirofumi
H
Ohba
Keisuke
K
Matsuzawa
Yasushi
Y
Konishi
Masaaki
M
Nozaki
Toshimitsu
T
Horibata
Yoko
Y
Kaikita
Koichi
K
Sumida
Hitoshi
H
Takeya
Motohiro
M
Ogawa
Hisao
H
D052242:Adiponectin; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics*; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010880:Piperidines / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D043882:Receptors, Cannabinoid / Q000235:genetics* / Q000378:metabolism; D000077285:Rimonabant
D052242:Adiponectin; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D002784:Cholesterol; D000077285:Rimonabant