Cannabinoid-2 Receptor Activation Protects Against Infarct and Ischemia–Reperfusion Heart Injury
Cannabinoid-2 Receptor Activation Protects Against Infarct and Ischemia–Reperfusion Heart Injury
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DOI：
10.1097/fjc.0b013e3182418997
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发表时间：
2012-04
影响因子：
3
通讯作者：
Peng-Fei Wang;Li-sheng Jiang;J. Bu;Xiaojing Huang;Wei Song;Yong-ping Du;B. He
中科院分区：
文献类型：
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作者：
Peng-Fei Wang;Li-sheng Jiang;J. Bu;Xiaojing Huang;Wei Song;Yong-ping Du;B. He
翻译后摘要：据报道，内源性大麻素系统在心肌缺血-再灌注（IR）损伤和保护心脏损伤。因此，我们观察了急性心肌梗死（AMI）和心肌IR损伤过程中内源性大麻素水平的变化，并评估了大麻素-2（CB 2）受体在梗死和IR心脏损伤中的作用。与16例冠状动脉造影正常的对照组相比，23例AMI患者梗死侧冠状动脉中的内源性大麻素2-花生四烯酸甘油水平显著升高，梗死侧冠状动脉和桡动脉中的活性氧和肿瘤坏死因子水平均升高。然后，将35只C57 BL/6 J小鼠制成SHAM、AMI和IR模型。AMI组和IR组分别给予CB 2选择性激动剂HU 308（（+）-（1aH，3 H，5aH）-4-[2，6-二甲氧基-4-（1，1-二甲基庚基）苯基]-6，6-二甲基二环[3.1.1]庚-2-烯-2-甲醇），有或没有CB 2-选择性拮抗剂AM 630 [6-碘-2-甲基-1-[2-甲基-1-[3-（三氟甲基）苯基]氨基]-2-甲基]-N-甲基-N-苯基]-N-甲基-N-甲基（4-吗啉基）乙基]-1H-吲哚-3-基]（4-甲氧基苯基）甲酮腹腔注射。与SHAM相比，AMI/IR动物中大麻素CB 1/CB 2受体蛋白的表达上调; 2-花生四烯酰甘油和花生四烯酰胺的产生以及活性氧和肿瘤坏死因子的释放也增加。HU 308可显著降低AMI/IR动物的梗死面积、活性氧和肿瘤坏死因子-α水平。然而，这些作用被AM 630阻断。总之，内源性大麻素系统在AMI和IR期间被激活，并且CB 2受体激活产生保护作用，从而为治疗这些疾病提供了新的药物靶点。
Abstract: Endocannabinoid system is reported to be activated during myocardial ischemia–reperfusion (IR) injury and protects against heart injury. We, therefore, observed changes in endocannabinoids levels during acute myocardial infarction (AMI) and myocardial IR injury and evaluated the role of cannabinoid-2 (CB2) receptor in infarct and IR heart injury. In contrast to 16 control patients with normal coronary artery angiogram, the endocannabinoid 2-arachidonoylglycerol level in the infarct-side coronary artery of 23 AMI patients increased significantly, with increased reactive oxygen species and tumor necrosis factor- levels in both infarct-side coronary artery and radial artery. Then, 35 C57BL/6J mice were made into SHAM, AMI, or IR models. AMI and IR groups were treated with CB2-selective agonist HU308 ((+)-(1aH,3H,5aH)-4-[2,6-dimethoxy-4-(1,1-dimethylheptyl)phenyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-carbinol), with or without CB2-selective antagonist AM630 [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone through intraperitoneal injection. Compared with the SHAM, expressions of cannabinoid CB1/CB2 receptor proteins in AMI/IR animals were upregulated; production of 2-arachidonoylglycerol and anandamide and release of reactive oxygen species and tumor necrosis factor- also increased. HU308 significantly decreased the infarct size and the levels of reactive oxygen species and tumor necrosis factor- in AMI/IR animals. However, these effects were blocked by AM630. In conclusion, the endocannabinoid system was activated during AMI and IR, and CB2 receptor activation produces a protective role, thus offering a novel pharmaceutical target for treating these diseases.