长春西汀通过SIRT1介导的HMGB1脱乙酰化在重症急性胰腺炎后心肌损伤中发挥保护作用

    Vinpocetine plays a protective role in myocardial injury after severe acute pancreatitis through SIRT1-mediated deacetylation of HMGB1

      摘要
    • 摘要:
      目的 探讨长春西汀缓解重症急性胰腺炎（severe acute pancreatitis，SAP）的疗效和药理学机制。
      方法 40只SD大鼠随机分为4组，Control组、Sham组、SAP Model组和长春西汀治疗（SAP Model+Vinpocetine）组，每组10只。超声心动图评估大鼠心脏功能。H&E染色测定大鼠心肌组织形态学变化。ELISA测定大鼠血清炎症因子TNF-α、IL-1β、IL-6、肌酸激酶同工酶（CK-MB）和高迁移率组盒-1（high mobility group box-1，HMGB1）的水平。Western blot法测定大鼠胰腺组织沉默信息调节因子1（silent information regulator 1，SIRT1）和HMGB1的水平。免疫共沉淀（co-IP）法测定SIRT1和HMGB1的直接作用方式。
      结果 Control组和Sham组心肌纤维排列紧密、规则，心肌纤维之间无大量组织间隙；SAP Model组心肌纤维排列杂乱，心肌纤维之间存在大量组织间隙；SAP Model+Vinpocetine组心肌纤维排列略杂乱，心肌纤维之间的组织间隙少于SAP Model组。与Control组相比，SAP Model组心率、左心室舒张压明显上升（P<0.05），左心室射血分数、左心室收缩分数和左心室收缩压明显降低（P<0.05）；血清TNF-α、IL-1β、IL-6、CK-MB和HMGB1的水平明显上升（P<0.05）；胰腺组织HMGB1的水平明显升高，SIRT1的水平明显降低（P<0.05）。与SAP Model组相比，SAP Model+Vinpocetine组明显逆转了上述指标（P<0.05）。Sham组和Control组上述指标无明显差异。在HEK 293T细胞中共转染和表达Myc-SIRT1和Flag-HMGB1-A，使用抗Flag抗体下拉的蛋白质中可以检测到含Myc标签的蛋白质。与Control组相比，LPS组HEK 293T细胞中HMGB1表达水平明显增强，SIRT1表达水平明显降低（P<0.05）。
      结论 长春西汀通过上调SIRT1对HMGB1去乙酰化修饰并下调HMGB1的水平缓解SAP大鼠模型心肌损伤，保护心脏功能。

       

      Abstract:
      AIM To investigate the effects and pharmacological mechanisms of vinpocetine in patients with severe acute pancreatitis (SAP).
      METHODS Forty SD rats were randomly divided into 4 groups: control group, sham group, SAP model group and SAP model+vinpocetine group, with 10 rats in each group. Echocardiography was used to evaluate rat cardiac functions and H&E staining was used to detect myocardial tissue morphological changes. Serum levels of inflammatory cytokines TNF-α, IL-1β, IL-6 and HMGB1 were determined by ELISA, the levels of SIRT1 and HMGB1 in rats pancreatic tissues were determined by Western blot and the direct interaction of SIRT1 and HMGB1 was determined by co-IP.
      RESULTS Compared with those in control group, the heart rate and left ventricular diastolic blood pressure in SAP model group were significantly increased (P<0.05), left ventricular ejection fraction, left ventricular fractional shortening and left ventricular systolic blood pressure were significantly decreased (P<0.05). The levels of serum TNF-α, IL-1β, IL-6, creatine kinase isoenzyme (CK-MB) and HMGB1 (high mobility group box-1) were significantly increased (P<0.05). The level of HMGB1 in rat pancreatic tissues was significantly increased and the level of SIRT1 (silent information regulator 1) was significantly decreased (P<0.05). Compared with SAP model group, SAP model+vinpocetine group significantly reversed the above indexes (P<0.05). There was no significant difference between sham group and control group . Myc-SIRT1 and Flag-HMGB1-A were co-transfected and expressed in HEK 293T cells, and proteins containing Myc tags could be detected in the proteins pulled down by anti-Flag antibodies. Compared with those in control group, the expression level of HMGB1 in LPS group of HEK 293T cells was significantly increased, and the expression level of SIRT1 was significantly decreased (P<0.05).
      CONCLUSION Vinpocetine alleviates myocardial injury and protects cardiac functions in SAP rat model by up-regulating SIRT1 to deacetylate HMGB1 and down-regulate HMGB1.

       

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