达格列净基于BMP2抑制NLRP3/Caspase-1介导的细胞焦亡治疗糖尿病合并心衰

    Daggligin inhibits NLRP3/Caspase-1 mediated pyroptosis through BMP2 in the treatment of diabetes with heart failure

      摘要
    • 摘要:
      目的 从细胞焦亡角度探讨达格列净（Dapagliflozin，DAP）治疗糖尿病合并心衰的可能作用机制。
      方法 将30只大鼠随机分为对照组、模型组和DAP组。通过腹腔注射STZ构建糖尿病大鼠模型，通过腹腔注射多柔比星（Doxorubicin，DOX）构建心力衰竭大鼠模型。观察大鼠精神、活动、饮食及排泄情况；检测各组大鼠心脏功能参数；通过苏木精-伊红（hematoxylin-eosin，HE）、马松（Masson）和天狼星红（Sirius red）染色评估各组大鼠心肌组织病理学结果；通过ELISA检测各组大鼠血清心房利钠肽（atrial natriuretic peptide, ANP）、脑利钠肽（brain natriuretic peptide，BNP）和骨形态发生蛋白2(bone morphogenetic protein-2，BMP-2)的表达水平；通过Western blot检测大鼠心肌组织BMP-2、NOD样受体热蛋白结构域相关蛋白3（NOD-like receptor thermal protein domain associated protein 3, NLRP3）、含半胱氨酸的天冬氨酸蛋白水解酶1（cysteinyl aspartate specific proteinase 1，Caspase-1）和gasdermin D（GSDMD）蛋白水平；通过ELISA检测各组大鼠血清白细胞介素-1β (interleukin-1β，IL-1β）和白细胞介素-18 (interleukin-18，IL-18）的表达水平。
      结果 DAP显著改善模型组大鼠精神、活动、饮食及排泄情况 ，增加模型组大鼠收缩末期压力（P<0.01）、心率（P<0.05）、每搏输出量（P<0.01）和射血分数（P<0.01）以及降低舒张末期压力（P<0.01）。此外，DAP显著减少模型组大鼠心肌组织纤维化面积（P<0.01），降低模型组大鼠血清中ANP（P<0.01）、BNP（P<0.01）和BMP-2（P<0.01）的表达，增加模型组大鼠心肌组织中BMP-2（P<0.01）的蛋白含量，降低模型组大鼠心肌组织中NLRP3（P<0.01）、Csapase-1（P<0.01）和GSDMD（P<0.01）蛋白含量，减少模型组大鼠血清中IL-1β（P<0.01）和IL-18（P<0.01）的含量。
      结论 DAP能够有效改善糖尿病合并心衰大鼠的心肌损伤，其机制可能与BMP2/NLRP3/Caspase-1通路抑制心肌细胞焦亡，减轻心肌内炎症水平有关。

       

      Abstract:
      AIM To explore the possible mechanism of Dapagliflozin (DAP) in the treatment of diabetes complicated with heart failure from the perspective of cell pyroptosis.
      METHOD Thirty rats were randomly divided into control group, model group and DAP group. The diabetic rat model was established by intraperitoneal injection of streptozotocin (STZ) and the heart failure rat model was established by intraperitoneal injection of doxorubicin (DOX). The rats’ spirit, activity, diet and excretion were observed and the cardiac function parameters of rats in each group were detected. The myocardial histopathological results of rats in each group were evaluated by HE, Masson and Sirius red staining. The expression levels of ANP, BNP and BMP-2 in serum of rats in each group were detected by ELISA and the protein levels of BMP-2, NLRP3, csapase-1 and GSDMD in rat myocardial tissue were detected by Western blot. The serum IL-1β and IL-18 expression levels of rats in each group was detected by ELISA.
      RESULTS DAP significantly improved the spirit, activity, diet and excretion, decreased the end systolic pressure (P<0.01), heart rate (P<0.05), stroke volume (P<0.01) and ejection fraction (P<0.01) and increased the end diastolic pressure (P<0.01) of rats in the model group. In addition, DAP significantly reduced the fibrotic area of myocardial tissue (P<0.01), decreased the expressions of serum ANP (P<0.01), BNP (P<0.01) and BMP-2 (P<0.01), increased the protein content of BMP-2 (P<0.01) in the myocardial tissue, decreased the protein content of NLRP3 (P<0.01), csapase-1 (P<0.01)and GSDMD (P<0.01) in the myocardial tissue, and decreased the serum IL-1β (P<0.01) and IL-18 (P<0.01) expression levels of the rats in the model group.
      CONCLUSION DAP effectively improves myocardial injury in diabetic rats with heart failure and its mechanism may be related to BMP2/NLRP3/Caspase-1 pathway inhibiting cardiomyocyte pyroptosis and reducing myocardial inflammation.

       

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