丹参-红花配伍调控未折叠蛋白应答改善糖尿病心肌病小鼠心脏功能研究

Study on the Combination of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos to Regulate Unfolded Protein Response and Improve Cardiac Function in Mice with Diabetic Cardiomyopathy

    摘要
  • 摘要:
      目的  探讨丹参-红花配伍口服给药对糖尿病心肌病小鼠的作用及机制。
      方法  将46只C57BL/6J小鼠, 分为空白对照组、糖尿病心肌病组、丹参-红花配伍短期治疗给药组、丹参-红花配伍长期预防给药组和恩格列净阳性药组。采用高脂饲料饲养(10周)结合STZ注射(120 mg·kg-1, 单次注射)的方法建立糖尿病心肌病小鼠模型。监测小鼠体质量、能量摄取、饮水量, 采用口服糖耐量试验(OGTT)和胰岛素耐量试验(ITT)评价小鼠葡萄糖代谢能力, 应用心脏超声技术测定小鼠心脏收缩功能(FS)和舒张功能(MV E/A), 采用分子生物学方法分析未折叠蛋白应答信号通路上IRE1、PERK、ATF6α、ATF4、Xbp1s、GRP94和GRP78等关键转录因子的基因及蛋白表达。
      结果  与糖尿病心肌病小鼠相比, 丹参-红花配伍长期预防给药小鼠的饮水量和血糖水平分别降低21.56%(P＜0.000 1)和28.82%(P＜0.000 1), 胰岛素水平上升43.63%(P＜0.05);OGTT和ITT的曲线下面积(AUC)分别下降16.56%(P＜0.05)和6.82%;FS和MV E/A分别增加32.86%(P＜0.001)和24.3%(P＜0.01), 左心室IRE1、Xbp1s、GRP78和GRP94的基因表达水平以及GRP78的蛋白表达水平均显著增加(P＜0.05)。丹参-红花配伍短期治疗给药对糖尿病心肌病小鼠的饮水量(降低10.46%, P＜0.05)、心脏舒张功能障碍(MV E/A增加17.87%, P＜0.01), 以及IRE1、ATF4、Xbp1s、GRP78和GRP94 mRNA以及GRP78蛋白表达水平(P＜0.05)有显著调控作用。
      结论  丹参-红花配伍口服给药对糖尿病心肌病小鼠具有显著改善作用。

     

    Abstract:
      OBJECTIVE  To explore the effects of oral administration of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos (DH) on mice with diabetic cardiomyopathy and the underlying mechanisms.
      METHODS  Forty-six C57BL/6J mice were divided into the control (CTL) group, diabetic cardiomyopathy (DCM) group, short-term DH administration (DCM-DHO) group, long-term DH administration (DCM-DHOL) group and empagliflozin positive drug (EMPA) group. A mouse model of diabetic cardiomyopathy was established using a high-fat diet (10 weeks) combined with STZ injection (120 mg·kg-1, single injection). The body weight, energy intake, and water consumption of mice were monitored and the glucose metabolism of mice was evaluated by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Cardiac systolic function (FS) and diastolic function (MV E/A) of mice were measured by echocardiography. Molecular biological methods were used to analyze the gene and protein expression of key transcription factors such as IRE1, PERK, ATF6α, ATF4, Xbp1s, GRP94 and GRP78 in unfolded protein response signal pathway.
      RESULTS  Compared with diabetic cardiomyopathy mice, the water consumption and blood glucose level of DCM-DHOL mice were decreased by 21.56% (P < 0.000 1) and 28.82% (P < 0.000 1), respectively; the insulin level was increased by 43.63% (P < 0.05) and the areas under the curves of OGTT and ITT were decreased by 16.56% (P < 0.05) and 6.82%, respectively; the FS and MV E/A were increased by 32.86% (P < 0.001) and 24.3% (P < 0.01), respectively; the gene expression levels of left ventricular IRE1, Xbp1, GRP78 and GRP94 (P < 0.05) and the protein expression level of GRP78 (P < 0.05) were also significantly increased. In DCM-DHO mice, the water consumption decreased by 10.46% (P < 0.05), cardiac diastolic function MV E/A increased by 17.87% (P < 0.01), and the mRNA levels of IRE1, Xbp1s, GRP78 and GRP94 and protein expression of GRP78 (P < 0.05) were significantly improved as compared with diabetic cardiomyopathy mice.
      CONCLUSION  Oral administration of DH has a significant improvement effect on diabetic cardiomyopathy mice.

     

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