达格列净改善2型糖尿病小鼠心肌损伤互作分子网络研究

Interaction molecular network study of Dapagliflozin in improving myocardial injury in type 2 diabetic mice

目的探寻达格列净改善糖尿病心肌损伤的调控分子,阐明其治疗新靶点。方法选取20只6~8周龄的C57BL6J雄性小鼠给予高脂饮食(HFD,甘油三酯60%)喂养造模。将成模小鼠随机分成两组,达格列净干预组给予达格列净10 mg/(kg·d),HFD单独喂养组给予正常饮用水。取两组小鼠的心脏组织进行RNA提取和转录组芯片(Agilent Mouse ceRNA Microarray 2019)分析。获得两组小鼠差异表达的mRNA。进一步通过生物信息学分析明确差异表达显著的信号转导通路及相关调控基因。结果将提取的各心肌组织RNA应用样本变异性检测确认了两组小鼠心脏组织标本的有效性。转录组学分析显示,与HFD单独喂养组比较,达格列净干预组小鼠心肌组织中共获得71个差异表达显著基因,其中,上调表达23个,下调表达48个。进一步应用GO和KEGG生物信息学软件分析证实,达格列净干预组小鼠炎性相关基因显著降低,而Toll样受体相关的信号转导通路基因活化上调。结论达格列净改善糖尿病心肌损伤是通过抑制炎症分子和上调Toll样受体相关的信号转导通路实现的。

Objective To try to find the regulatory molecules of Dapagliflozin in improving diabetic myocardial injury,and to clarify its new therapeutic targets.Methods Twenty male C57 BL6 J mice aged 6 to 8 weeks were fed high-fat diet(HFD,triglyceride 60%)for modeling.Model mice were randomly divided into two groups,dagagligin intervention group was given dagagligin 10 mg/(kg·d),and HFD alone feeding group was given normal drinking water.The heart tissues of the two groups of mice were extracted for RNA and analyzed by Agilent Mouse ceRNA Microarray 2019.The differentially expressed mRNAs of the two groups of mice were obtained.Further bioinformatics analysis was used to identify the significantly differentially expressed signal transduction pathways and related regulatory genes.Results The extracted myocardial tissue RNA was applied to the sample variability test to confirm the validity of the two mouse heart tissue samples.Transcriptome analysis showed that compared with the HFD alone feeding group,a total of 71 differentially expressed genes were obtained in the myocardium of mice in dagagligin intervention group,of which 23 were up-regulated and 48 were down-regulated.Further application of GO and KEGG bioinformatics software analysis confirmed that the inflammatory-related genes in the Dapagliflozin intervention group were significantly reduced,while the activation of Toll-like receptor-related signal transduction pathway genes was up-regulated.Conclusion Dapagliflozin improves diabetic myocardial injury by inhibiting inflammatory molecules and up-regulating Toll-like receptor-related signal transduction pathways.