Geriatric Department, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, 158 Shangtang Road, Zhejiang, Hangzhou, China.
Department of Emergency, the Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Zhejiang, Hangzhou, China.
Inflammation. 2019 Jun;42(3):904-914. doi: 10.1007/s10753-018-0945-x.
The administration of cannabinoid receptor 2 (CB2R) agonist has been reported to produce a cardioprotective effect against the pathogenesis and progression of myocardial infarction (MI). Here in this study, we investigated the specific mechanism related to inflammatory suppression. JWH-133 was used for the activation of CB2R. MI mice models and cardiomyocytes under oxygen-glucose deprivation (OGD) challenge were used for the in vivo and in vitro studies, respectively. Detection of cardiac infarct size and levels of myocardial enzymes as well as echocardiographic examination were applied to assess MI severity and cardiac function. Cell viability and lactate dehydrogenase (LDH) release were detected in vitro. Real-time-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the levels of proinflammatory cytokines. Western blot was used for the analysis of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. We found that the administration of CB2R agonist attenuated the severity of MI through reducing infarct size ratio and levels of myocardial enzymes and improved cardiac function in ejection fraction (EF), fractional shortening (FS), left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD) in MI mice. JWH-133 also produced a cardioprotective effect in murine primary cardiomyocytes by improving cell viability and LDH release. JWH-133 largely reduced the production and secretion of proinflammatory cytokines, which was significantly attenuated by AM630. HU308 showed the same effects as JWH-133. Taken together, we demonstrated for the first time the cardioprotective effect of CB2R agonist and its NLRP3 inflammasome-related mechanism in MI.
大麻素受体 2（CB2R）激动剂的给药已被报道可产生针对心肌梗死（MI）发病机制和进展的心脏保护作用。在本研究中，我们研究了与炎症抑制相关的特定机制。JWH-133 用于激活 CB2R。使用 MI 小鼠模型和氧葡萄糖剥夺（OGD）挑战下的心肌细胞进行体内和体外研究。分别应用检测心肌梗塞面积和心肌酶水平以及超声心动图检查来评估 MI 严重程度和心脏功能。体外检测细胞活力和乳酸脱氢酶（LDH）释放。实时聚合酶链反应（RT-PCR）和酶联免疫吸附测定（ELISA）用于检测促炎细胞因子的水平。Western blot 用于分析 NOD 样受体家族，富含吡喃结构域的 3（NLRP3）炎性小体激活。我们发现，CB2R 激动剂的给药通过减少梗塞面积比和心肌酶水平减轻了 MI 的严重程度，并改善了 MI 小鼠的心脏功能，射血分数（EF），分数缩短（FS），左心室收缩末期直径（LVESD）和左心室舒张末期直径（LVEDD）。JWH-133 还通过改善细胞活力和 LDH 释放对原代心肌细胞产生了心脏保护作用。JWH-133 大大减少了促炎细胞因子的产生和分泌，而 AM630 则明显减弱了这一作用。HU308 表现出与 JWH-133 相同的作用。总之，我们首次证明了 CB2R 激动剂在 MI 中的心脏保护作用及其与 NLRP3 炎性小体相关的机制。
