Wu Aiping, Hu Pengfei, Lin Jian, Xia Wan, Zhang Rui
Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China.
Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
Front Pharmacol. 2018 Nov 6;9:1292. doi: 10.3389/fphar.2018.01292. eCollection 2018.
Cannabinoid receptor 2 (CB) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB in diabetic cardiomyopathy (DCM) and its underlying mechanisms. HU308 was used for the selective activation of CB. Bafilomycin A1 was used for the blockade of autophagy and compound C was used to inhibit AMPK signaling. An streptozotocin (STZ)-induced mice model and high glucose (HG)-challenged cardiomyocytes were applied for study. Cardiac function was detected by echocardiography and Western blot for the detection of autophagy-related and its signaling-related proteins. Transmission electron microscopy was used for the analysis of autophagosome number. Cell viability was detected by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. We found that activating CB by HU308 improved cardiac function in DCM as well as cell viability in cardiomyocytes under HG challenge, while the administration of bafilomycin A1 attenuated the protective effects. HU308 enhanced the level of autophagy in the heart tissues from DCM mice as well as cardiomyocytes under HG challenge. HU308 triggered the AMPK-mTOR-p70S6K signaling pathway, while the administration of compound C attenuated the cardio-protective effect of HU308 in cardiomyocytes under HG challenge. In conclusion, we initially demonstrated that activating CB produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.
据报道，大麻素受体2（CB）在诸如心肌梗死等心血管疾病中发挥心脏保护作用。在本研究中，我们探究了CB在糖尿病性心肌病（DCM）中的作用及其潜在机制。使用HU308选择性激活CB。使用巴弗洛霉素A1阻断自噬，使用化合物C抑制AMPK信号传导。采用链脲佐菌素（STZ）诱导的小鼠模型和高糖（HG）刺激的心肌细胞进行研究。通过超声心动图检测心脏功能，采用蛋白质免疫印迹法检测自噬相关及其信号传导相关蛋白。使用透射电子显微镜分析自噬体数量。通过细胞计数试剂盒-8（CCK-8）和乳酸脱氢酶（LDH）释放试验检测细胞活力。我们发现，HU308激活CB可改善DCM小鼠的心脏功能以及HG刺激下心肌细胞的活力，而给予巴弗洛霉素A1可减弱这种保护作用。HU308可增强DCM小鼠心脏组织以及HG刺激下心肌细胞的自噬水平。HU308触发AMPK-mTOR-p70S6K信号通路，而给予化合物C可减弱HU308对HG刺激下心肌细胞的心脏保护作用。总之，我们首次证明，激活CB通过诱导AMPK-mTOR-p70S6K信号介导的自噬，对DCM以及HG刺激下的心肌细胞产生心脏保护作用。
