目的 基于过氧化物酶体增殖物激活受体 γ（PPARγ）/过氧化物酶体增殖物激活受体 γ 辅助激活因子 1α （PGC-1α）通路探究丹参素对糖尿病心肌病（DCM）大鼠心肌线粒体功能的影响。方法 将大鼠随机分为正常 组、模型组、丹参素低剂量组（5 mg·kg-1 ）、丹参素中剂量组（10 mg·kg-1 ）、丹参素高剂量组（20 mg·kg-1 ）、二甲 双胍组（140 mg·kg-1 ）、丹参素高剂量+GW9662 组（20 mg·kg-1丹参素+1 mg·kg-1 GW9662），每组 12 只。除正常 组外，其余各组均采用高糖高脂饲料喂养联合腹腔注射链脲佐菌素的方法构建 DCM 大鼠模型。模型复制成功 后，各组按照上述设定剂量灌胃给药，每日 1 次，连续 6 周。采用动物血糖仪检测空腹血糖值；超声心动图评 估大鼠心功能，包括左室短轴缩短率（LVFS）、左室射血分数（LVEF）；HE 染色法观察心肌组织病理变化；透 射电镜观察心肌组织线粒体超微结构；JC-1 染色法检测心肌细胞线粒体膜电位；通过试剂盒检测心肌组织中 三磷酸腺苷（ATP）含量及活性氧（ROS）的表达水平；Western Blot 法检测心肌组织中 PPARγ、PGC-1α 蛋白表 达水平。结果 与正常组比较，模型组大鼠的空腹血糖水平明显升高（P＜0.05），LVFS、LVEF 明显降低（P＜ 0.05）；心肌组织明显受损，心肌线粒体肿胀；心肌细胞线粒体膜电位未降低细胞的百分比明显降低（P＜ 0.05）；心肌组织中 ATP 含量明显降低（P＜0.05），ROS 表达水平明显升高（P＜0.05）；心肌组织中 PPARγ、 PGC-1α 蛋白表达明显下调（P＜0.05）。与模型组比较，丹参素各剂量组及二甲双胍组大鼠空腹血糖水平明显 降低（P＜0.05），LVFS、LVEF 明显升高（P＜0.05）；心肌组织损伤减轻，心肌线粒体结构损伤有所减轻；心肌 细胞线粒体膜电位未降低细胞的百分比明显升高（P＜0.05）；心肌组织中 ATP 含量明显升高（P＜0.05），ROS 表达水平明显降低（P＜0.05）；心肌组织中 PPARγ、PGC-1α 蛋白表达明显上调（P＜0.05）。与丹参素高剂量组 比较，丹参素高剂量+GW9662 组大鼠空腹血糖水平明显升高（P＜0.05），LVFS、LVEF 明显降低（P＜0.05）；心 肌组织损伤、心肌线粒体结构损伤加重，心肌线粒体肿胀；心肌细胞线粒体膜电位未降低细胞的百分比明显降 低（P＜0.05）；心肌组织中 ATP 含量明显降低（P＜0.05），ROS 表达水平明显升高（P＜0.05）；心肌组织中 PPARγ、PGC-1α 蛋白表达明显下调（P＜0.05）。结论 丹参素改善 DCM 大鼠线粒体功能可能与激活 PPARγ/ PGC-1α 通路有关。

Objective To explore the effect of Danshensu on myocardial mitochondrial function in diabetes cardiomyopathy（DCM） rats based on peroxisome proliferator-activated receptor γ（PPARγ）/peroxisome proliferator-activated receptor γ co-activator-1α （PGC-1α） pathway. Methods Rats were randomly separated into normal group， model group， low- （5 mg·kg-1 ）， medium- （10 mg·kg-1 ） and high- （20 mg·kg-1 ） dose Danshensu groups，metformin group （140 mg·kg-1 ），as well as high-dose Danshensu+GW9662 group （20 mg·kg-1 Danshensu+ 1 mg·kg-1 GW9662），with 12 rats in each group. Except for the normal group，rats in other groups were fed with high-glucose and high-fat diet combined with intraperitoneal injection of streptozotocin to construct a DCM model. After successful modeling，the rats were administered corresponding drug once a day for six weeks. Fasting blood glucose values were detected by blood glucose meter. Echocardiography was applied to evaluate cardiac function of rats including left ventricular fractional shortening （LVFS） and left ventricular ejection fraction （LVEF） . HE staining was applied to detect pathological changes in myocardial tissue. Transmission electron microscopy was applied to observe mitochondrial structure of myocardial tissue. JC-1 staining was applied to detect mitochondrial membrane potential in rat cardiomyocytes. The kit was applied to detect adenosine triphosphate （ATP） content and reactive oxygen species （ROS） expression in myocardial tissue. Western Blot was applied to detect the protein expression of PPARγ and PGC-1α in myocardial tissue. Results Compared with normal group，fasting blood glucose in model group was significantly increased （P＜0.05），LVFS and LVEF were significantly decreased （P＜0.05） . It was found that myocardial tissue was obviously damaged and myocardial mitochondria became swollen. The percentage of non-deleted cardiomyocyte mitochondrial membrane potential was significantly decreased （P＜0.05） . ATP content in myocardial tissue was significantly decreased （P＜0.05），ROS expression was significantly increased （P＜0.05） . The protein expressions of PPARγ and PGC-1α in myocardial tissue were significantly downregulated （P＜0.05） . Compared with model group， fasting blood glucose levels in Danshensu and metformin groups were significantly decreased （P＜0.05），while LVFS and LVEF were significantly increased （P＜0.05） . It was found that myocardial tissue damage and mitochondrial structure damage were alleviated. The percentage of non-deleted cardiomyocyte mitochondrial membrane potential was significantly increased （P＜0.05） . ATP content in myocardial tissue was significantly increased （P＜0.05），ROS expression was significantly decreased （P＜0.05） . The protein expressions of PPARγ and PGC-1α in myocardial tissue were significantly upregulated （P＜0.05） . Compared with high-dose Danshensu group，fasting blood glucose level in high-dose Danshensu+GW9662 group was significantly increased （P＜0.05）， LVFS and LVEF levels were significantly decreased （P＜0.05） . Damage of myocardial tissue and myocardial mitochondria structure became serious and myocardial mitochondria was obviously swollen. The percentage of non-deleted cardiomyocyte mitochondrial membrane potential was significantly decreased （P＜0.05） . ATP content in myocardial tissue was significantly decreased （P＜0.05），ROS expression was significantly increased （P＜0.05）. The protein expressions of PPARγ and PGC-1α in myocardial tissue were significantly downregulated （P＜0.05）. Conclusion Danshensu improves mitochondrial function in DCM rats， which may be related to the activation of the PPARγ/PGC-1α pathway.

R285.5

2022年度湖北省教育厅科学技术研究项目（B2022518）