κ-阿片受体激活抗糖尿病心肌损伤的作用

顾晓明; 史睿; 罗乐金; 郭浩然; 安睿; 刘振华; 王渊博; 冯娜; 贾敏; 李娟; 牛军; 张淑苗

doi:10.12125/j.chj.20180405

κ-阿片受体激活抗糖尿病心肌损伤的作用

Effect of κ-opioid receptor activation on myocardial damage caused by diabetes mellitus

摘要

摘要:
目的探讨κ-阿片受体在抗糖尿病（diabetes mellitus, DM）心肌损伤中的作用及可能机制。
方法将C57BL/6J小鼠随机分为3组，即正常对照（Con）组、糖尿病模型（DM）组、糖尿病+κ-阿片受体激动剂U50, 488H（DM+U50, 488H）组。小鼠腹腔注射链脲佐菌素（streptozotocin，STZ，150 mg/kg）和高脂饮食结合的方式诱导DM模型，STZ注射1周后检测空腹血糖水平大于16.7 mmol/L的小鼠随机分为DM组和DM+U50, 488H组；这两组小鼠高脂饲养7周后，DM+U50, 488H组给予κ-阿片受体激动剂U50, 488H治疗1周，共计9周。实验中观察各组小鼠的一般体征，实验结束后检测各组小鼠的血糖和胰岛素水平、心脏结构和功能、心肌细胞凋亡、心肌组织和体液因子中氧化应激指标的变化。
结果与CON比较，DM组小鼠血糖水平显著增加（P < 0.01）、血清胰岛素水平明显降低（P < 0.01），心脏功能显著下降（P < 0.01），心肌细胞凋亡增加（P < 0.01），血清和心肌组织中丙二醛（MDA）的水平均显著增加（P < 0.01），血清或心肌组织中总抗氧化物（T-AOC）、超氧化物歧化酶（superoxide dismutase, SOD）、过氧化氢酶（catalase, CAT）、谷胱甘肽过氧化物酶（glutathione peroxidase, GSH）等因子水平则显著降低（P < 0.01）；κ-阿片受体激动剂U50, 488H可以显著降低糖尿病小鼠的血糖水平（P<0.01）、增加其血清胰岛素水平（P < 0.01），使糖尿病小鼠心脏功能显著增加（P < 0.01），减少心肌细胞凋亡（P < 0.01），降低血清和心肌组织中MDA的水平，增加血清或心肌组织中T-AOC、SOD、CAT、GSH等因子的水平（P < 0.05或P < 0.01）。
结论 κ-阿片受体激活具有明显改善糖尿病小鼠心肌损伤的作用，其作用机制是否与抗氧化应激、提高抗氧化物活力有关有待进一步证实。

Abstract:
AIM To study the effects of κ-opioid receptors on myocardial damage mediated by diabetic mellitus and its underlying mechanism.
METHODS C57BL/6J mice were randomly divided into three groups: a control(Con) group, a diabetic mellitus (DM) group, and DM+U50, 488H (a κ-opioid receptor selective agonist) group. Diabetic mellitus models were established by intraperitoneal injection of streptozotocin (150 mg/kg) and a high fat diet for 7 weeks. Mice in the DM + U50, 488H group were treated with U50, 488H (1.5 mg/kg, i.i) for 1 wk. General physical signs were recorded during the experiment. Fasting blood glucose (FBG) was measured by glucometer and serum insulin was detected by kit. The structure and function of the heart were measured by echocardiography. Myocardial apoptosis was detected by a TUNEL kit and indexes of oxidative stress were measured by Elisa kit.
RESULTS Compared with the Con group, FBG was increased (P < 0.01), wheras serum insulin was decreased significantly (P < 0.01). MDA activity in serum and myocardium were increased (P < 0.01). Total antioxidants content (T-AOC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH) activity (or content) were decreased significantly (P < 0.01). There was an increased myocardial apoptosis (P < 0.01) and a decreased cardiac function in the DM group (P < 0.01). After treatment with U50, 488H, the above effects were abrogated (P < 0.01), which was accompanied by a decreased myocardial apoptosis (P < 0.01) and an increased cardiac function in the DM+U50, 488H group (P < 0.01).
CONCLUSION κ-opioid receptor activation ameliorates myocardial damage caused by diabetic mellitus and further study is needed to demonstrate whether the role of κ-opioid receptor activation is mediated or modulated by inhibiting oxidative stress and improving activity of antioxidants.

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