Activated Endocannabinoid System in Coronary Artery Disease and Antiinflammatory Effects of Cannabinoid 1 Receptor Blockade on Macrophages
Activated Endocannabinoid System in Coronary Artery Disease and Antiinflammatory Effects of Cannabinoid 1 Receptor Blockade on Macrophages
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DOI：
10.1161/circulationaha.108.811992
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发表时间：
2009-01-06
期刊：
影响因子：
37.8
通讯作者：
Ogawa, Hisao
中科院分区：
文献类型：
--
作者：
Sugamura, Koichi;Sugiyama, Seigo;Ogawa, Hisao
背景--用利莫那班阻断大麻素1(CB1)受体是肥胖的一种临床治疗策略。最近，内源性大麻素系统在外周器官中的作用已被描述。我们试图确定内源性大麻素系统是否参与人类动脉粥样硬化，以及阻断CB1受体是否可以调节巨噬细胞的促炎活性。方法和结果-不稳定型心绞痛患者冠状动脉粥样硬化切除标本中CB1受体的mRNA表达水平显著高于稳定型心绞痛患者(3.62+/-2.96倍；n=7；P<；0.05)。冠状动脉免疫反应面积分析显示，CB1受体在脂类斑块中的表达高于纤维斑块，尤其是CD68巨噬细胞(9.5+/-1.2%vs0.6+/-0.6%；n=5；P<；0.01)。有冠心病组(n=20)的血内源性大麻素水平显著高于无冠心病组(中位数[四分位数范围]：安非他明，1.048 pmoL/m L[0.687~1.387 pm o l/m L]比0.537 pm o l/m L[0.468~0.857 p m o l/m L]，P<；0.05)。在培养的巨噬细胞中，CB1受体的表达在单核-巨噬细胞分化过程中显著增加(1.78+/-0.13倍；n=6；P<；0.01)。阻断巨噬细胞CB1受体可引起胞浆内cAMP显著升高(29.9+/-13.0%；n=4；P<0.01)，抑制c-jun氨基末端激酶的磷酸化(-19.1+/-12.6%，n=4；P<；0.05)，并导致促炎介质的产生显著减少(IL-1β，-28.9+/-10.9%；IL-6，-24.8+/-7.6%；白介素8，-22.7+/-5.2%；肿瘤坏死因子-α，-13.6+/-4.8%；基质金属蛋白酶-9，-16.4+/-3.8%；n=4~8；P<；0.01)。CB1受体阻断剂对巨噬细胞具有抗炎作用，可能对动脉粥样硬化的形成有一定的促进作用。(发行量。2009；119：28-36。)
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.Methods and 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-1 beta, -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. (Circulation. 2009; 119: 28-36.)