Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages.
BACKGROUND
Cannabinoid 1 (CB1) receptor blockade with rimonabant represents a clinical therapeutic strategy for obesity. Recently, the role of the endocannabinoid system has been described in peripheral organs. We sought to determine whether the endocannabinoid system could be involved in human atherosclerosis and whether CB1 receptor blockade could modulate proinflammatory activity in macrophages.


RESULTS
mRNA expression levels of CB1 receptor in coronary atherectomy samples were significantly higher in patients with unstable angina than in those with stable angina (3.62+/-2.96-fold; n=7; P<0.05). Immunoreactive area analysis of the coronary artery showed that CB1 receptor expression was greater in lipid-rich atheromatous plaques than in fibrous plaques, especially in CD68 macrophages (9.5+/-1.2% versus 0.6+/-0.6%; n=5; P<0.01). Levels of blood endocannabinoids were significantly higher in patients with coronary artery disease (n=20) than those without coronary artery disease (n=20) (median [interquartile range]: anandamide, 1.048 pmol/mL [0.687 to 1.387 pmol/mL] versus 0.537 pmol/mL [0.468 to 0.857 pmol/mL], P<0.01; 2-arachidonoyl glycerol, 13.30 pmol/mL [6.65 to 16.21 pmol/mL] versus 7.67 pmol/mL [6.39 to 10.03 pmol/mL], P<0.05). In cultured macrophages, expression of CB1 receptor was significantly increased during monocyte-macrophage differentiation (1.78+/-0.13-fold; n=6; P<0.01). CB1 receptor blockade in macrophages induced a significant increase in cytosolic cAMP (29.9+/-13.0%; n=4; P<0.01), inhibited phosphorylation of c-Jun N-terminal kinase (-19.1+/-12.6%, n=4; P<0.05), and resulted in a significant decrease in the production of proinflammatory mediators (interleukin-1beta, -28.9+/-10.9%; interleukin-6, -24.8+/-7.6%; interleukin-8, -22.7+/-5.2%; tumor necrosis factor-alpha, -13.6+/-4.8%; matrix metalloproteinase-9, -16.4+/-3.8%; n=4 to 8; P<0.01).


CONCLUSIONS
Patients with coronary artery disease demonstrated the activation of the endocannabinoid system with elevated levels of blood endocannabinoids and increased expression of CB1 receptor in coronary atheroma. CB1 receptor blockade exhibited antiinflammatory effects on macrophages, which might provide beneficial effects on atherogenesis.
Sugamura
Koichi
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.
Sugiyama
Seigo
S
Nozaki
Toshimitsu
T
Matsuzawa
Yasushi
Y
Izumiya
Yasuhiro
Y
Miyata
Keishi
K
Nakayama
Masafumi
M
Kaikita
Koichi
K
Obata
Toru
T
Takeya
Motohiro
M
Ogawa
Hisao
H
D000789:Angina, Unstable / Q000276:immunology / Q000473:pathology; D015906:Angioplasty, Balloon, Coronary; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017225:Atherectomy, Coronary; D063385:Cannabinoid Receptor Modulators / Q000097:blood; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D063388:Endocannabinoids; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D009765:Obesity / Q000276:immunology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D014657:Vasculitis / Q000276:immunology / Q000473:pathology
D000893:Anti-Inflammatory Agents; D063385:Cannabinoid Receptor Modulators; D016207:Cytokines; D063388:Endocannabinoids; D008070:Lipopolysaccharides; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D000077285:Rimonabant