FGF21在依帕列净抑制心衰中的作用和机制研究

The role of FGF21 in inhibition of heart failure with empagliflozin and related mechanisms

本文旨在探究纤维母细胞生长因子21(fibroblast growth factor 21,FGF21)在依帕列净(empagliflozin,EMP)抑制心衰中的作用和相关机制。系统性FGF21敲除(FGF21 knockout,FGF21 KO)小鼠和对照野生型(wild type,WT)小鼠给予多柔比星(doxorubicin,Dox)诱导建立心衰模型,并采用EMP或安慰剂进行干预。实验结果显示,在WT和FGF21 KO小鼠中,Dox(5 mg·kg^(-1))均能够诱导产生典型的心衰症状;在WT小鼠中,给予造模小鼠EMP(10 mg·kg^(-1))干预,发现EMP可以显著改善由Dox引起的心脏功能异常,主要表现为改善心肌收缩功能、左心室射血分数和缩短分数的下降及心肌酶(天门冬氨酸氨基转移酶、肌酸激酶、羟丁酸脱氢酶和乳酸盐脱氢酶)含量的增加;此外,Dox引起的心脏纤维化、炎症和氧化应激也被EMP显著改善。但是在FGF21 KO小鼠中,EMP对于心衰的上述治疗作用被显著抑制。以上结果提示,EMP治疗心衰的功能依赖于FGF21,其作用机制可能与FGF21改善纤维化、炎症和氧化应激的作用有关。

The aim of this study is to investigate the role of fibroblast growth factor 21(FGF21)in empagliflozin(EMP)in treatment of heart failure and the related mechanisms.FGF21 knockout(FGF21 KO)and littermate wild-type(WT)mice induced by doxorubicin(Dox)were used to establish heart failure mouse model in vivo.The experiment process and animal welfare follow the regulations of Animal Ethics Committee of Hefei University of Technology strictly.The results suggest that Dox(5 mg·kg^(-1))induced typical heart failure symptoms in both WT and FGF21 KO mice.In WT mice,EMP(10 mg·kg^(-1))significantly improved Dox-induced cardiac atrophy,decreased myocardial systolic function,decreased left ventricular ejection fraction and shortened fraction;EMP treatment also significantly inhibited the increase of Dox-induced cardiotoxicity indexes(aspartate amino transferase,creatine kinase,hydroxybutyrate dehydrogenase,lactate dehydrogenase)in mice.Dox induced cardiac fibrosis,inflammation and oxidative stress were also significantly improved by EMP.However,in FGF21 KO mice,the therapeutic effects of EMP on heart failure was significantly inhibited.The results suggest that the function of EMP in treating heart failure partly depends on the presence of FGF21,and the mechanism may be related to the effect of FGF21 on improving fibrosis,inflammation and oxidative stress.