摘要
目的:探讨达格列净对1型糖尿病小鼠心肌损伤的影响及机制研究。方法:正常C57BL/6J雄性小鼠随机分为正常对照组(Control)、糖尿病心肌病组(DCM)和达格列净组(DAPA)。应用链脲佐菌素(STZ)诱导并给予维持饲料联合构建糖尿病模型。DAPA组给予10 mg·kg-1·d-1的达格列净灌胃,Control组与DCM组给予等体积0.9%氯化钠溶液灌胃。干预8周后,应用超声机来检测各组心功能;乳酸脱氢酶(LDH)检测心肌损伤;HE染色观察心脏形态;Masson、天狼星红染色观察心脏纤维化程度;TUNEL检测心肌凋亡;免疫组化检测NLRP3、Caspase-1、GSDMD、Collagen Ⅰ、Collagen Ⅲ、α-SMA、Fibronectin胶原表达情况;qPCR法检测Caspase-1、GSDMD、α-SMA、Fibronectin的mRNA基因表达含量;Western blot法检测心肌焦亡及纤维化相关蛋白NLRP3、Caspase-1、GSDMD、Collagen Ⅰ、Collagen Ⅲ、α-SMA、Fibronectin、IL-18蛋白表达水平。结果:与Control组比DCM组表现出异常超声心动图表征,血清乳酸脱氢酶升高,心脏组织结构异常,肌纤维排列紊乱,见明显的纤维增粗、断裂。心肌组织中凋亡染色强度增加,相关焦亡指标NLRP3、Caspase-1、GSDMD基因和蛋白表达升高,纤维化指标Collagen Ⅰ、Collagen Ⅲ、α-SMA、Fibronectin基因和蛋白表达升高。而DAPA组减弱了先前提到的参数的改变。结论:达格列净可以改善心肌纤维化及心肌焦亡程度从而改善糖尿病导致的心肌损伤。
AIM:To investigate the effect of dapagliflozin on myocardial injury in type 1 diabetes mice and its mechanism.METHODS:Normal C57BL/6J male mice were randomly divided into normal control group(Control),diabetes cardiomyopathy group(DCM)and dapagliflozin group(DAPA).The model of diabetes was induced by streptozotocin(STZ)and given maintenance feed.DAPA group was given 10 mg·kg^(-1)·d^(-1) of dapagliflozin by gavage,while control group and DCM group were given 0.9%sodium chloride solution by gavage.After 8 weeks of intervention,the cardiac function of each group was measured by ultrasound;Lactate dehydrogenase(LDH)was used to detect myocardial injury;HE staining was used to observe the cardiac morphology;Masson and Sirius red staining were used to observe the degree of cardiac fibrosis;TUNEL was used to detect myocardial apoptosis.The expressions of NLRP3,Caspase-1,GSDMD,Collagen I,Collagen III,α-SMA,Fibronectin,Caspase-1 and GSDMD analyzed by immunohistochemical staining.The expression levels of NLRP3,Caspase-1,GSDMD,Collagen I,Collagen III,α-SMA,Fibronectin and IL-18 were detected by Western blot.RESULTS:Compared with the control group,DCM group showed abnormal echocardiographic features,increased serum lactate dehydrogenase,abnormal cardiac tissue structure,disordered arrangement of muscle fibers,and obvious fiber thickening and fracture.The staining intensity of apoptosis in myocardial tissue increased,the expression of NLRP3,Caspase-1,GSDMD gene and protein increased,and the expression of Collagen I,Collagen III,α-SMA,fibronectin gene and protein increased.The DAPA group attenuated the previously mentioned parameter changes.CONCLUSION:Dapagliflozin can improve the degree of myocardial fibrosis and myocardial pyroptosis,thus improving the myocardial injury caused by diabetes.
作者
张雪娇
刘洁婷
李鲁新
陈培剑
丁明璐
孙梦伟
初彦辉
张珍
ZHANG Xuejiao;LIU Jieting;LI Luxin;CHEN Peijian;DING Minglu;SUN Mengwei;CHU Yanhui;ZHANG Zhen(College of Life Sciences,Mudanjiang Medical University,Mudanjiang 157011,Heilongjiang,China;The First Clinical Medical College,Mudanjiang Medical University,Mudanjiang 157011,Heilongjiang,China)
出处
《中国临床药理学与治疗学》
CAS
CSCD
2023年第3期257-265,共9页
Chinese Journal of Clinical Pharmacology and Therapeutics
基金
黑龙江省省属本科高校中央支持地方高校改革发展高水平人才项目(2020GSP09)
黑龙江省自然科学基金联合引导项目(LH2022H099)
黑龙江省普通本科高等学校青年创新人才培养计划项目(UNPYSCT-2020064)
黑龙江省教育厅省属高等学校基本科研业务费科研项目(2019-KYYWF-1005,2021-KYYWF-0519)
牡丹江市科技局科技指导项目(HT2020NS101,HT2020JG070)。
关键词
达格列净
糖尿病
心肌损伤
细胞焦亡
纤维化
dapagliflozin
diabetes
myocardial injury
cell apoptosis
fibrosis
