Abstract 3970: Activated Endocannabinoid System in Coronary Artery Disease and Anti-Inflammatory Effects of Cannabinoid 1 Receptor Blockade on Macrophages
Cannabinoid 1 receptor (CB1R) blockade with rimonabant represents a clinical therapeutic strategy for obesity. Recently, the role of endocannabinoid (EC) system has been described in peripheral organs. We hypothesized that CB1R are expressed in human coronary atheroma, suggesting a possible benefit of rimonabant against atherogenesis. mRNA expression levels of CB1R in human coronary atherectomy samples were significantly higher in unstable coronary artery disease (CAD) patients than stable CAD patients (9.84±8.03 vs. 2.72±2.20, n=7; P<0.05). Immunoreactive area analysis of human coronary artery showed CB1R to be expressed to a greater extent in lipid-rich atheromatous plaques than fibrous plaques (9.5±1.2% vs. 0.6±0.6%, n=5; P<0.01), especially in CD68-positive macrophages. CB1R expression significantly increased during monocyte-macrophage differentiation (+77.3±13.6%, P<0.01) and it was significantly augmented by macrophage colony-stimulating factor (+27.7±5.3%, P<0.01) and oxidized low density lipoprotein (+42.2±12.7%, n=6; P<0.01). An EC biosynthesizing enzyme (N-acyl-phosphatidyl-ethanolamine-selective phospholipase D : NAPE-PLD) was increased and a degrading enzyme (fatty acid amide hydrolase : FAAH) was reduced during macrophage-differentiation (NAPE-PLD: +45.0±9.6%, FAAH: −24.3±7.5%, n=6; P<0.01). The levels of blood ECs measured by LC/MS/MS were significantly higher in CAD patients than control (anandamide, 1.048 [0.687–1.387] vs. 0.537 [0.468 – 0.857]; 2-arachidonoyl glycerol, 13.30 [6.65–16.21] vs. 7.67 [6.39 –10.03] pmol/L, n=20; P<0.05). Treatment with rimonabant in lipopolysaccharide-stimulated macrophages resulted in a significant decrease in the production of inflammatory mediators (interleukin[IL]-1β, -48.9±4.7%; IL-8, −22.7±5.2%; tumor necrosis factor-α, −13.6±4.8%; matrix metalloproteinase-9, −16.4±3.8%, n=4; P<0.01). This study demonstrated the activation of EC system with increased expression of CB1R in human atherosclerosis and indicated that rimonabant exhibited anti-inflammatory effects on human macrophages. CB1R blockade might provide anti-atherosclerotic effects through modulation of the EC system in patients with CAD.