Effect Of GLP-1R Agonist On Doxorubicin-induced Cardiac Fibrillation In Rats

Objective: In this study,we established a rat model of myocardial fibrosis induced by doxorubicin and intervened with glucagon-like peptide-1 receptor agonist(GLP-1RA)to examine the effect and mechanism of GLP-1R agonist on doxorubicin-induced myocardial fibrosis in rats.Methods: 40 SD rats were randomly divided into four groups: normal group(N group),doxorubicin group(DOX group),doxorubicin + dulapeptide group(GLP-1RA group),doxorubicin + dulapeptide + Exendin(9-39)group(EX9-39 group).Adaptive feeding of rats for one week,doxorubicin(3mg/kg tiw)was used to establish the rat model of myocardial fibrosis,except N group.GLP-1RA rats received a dose of 1mg/kg/d of dulapeptide by subcutaneous injection and EX9-39 rats received a dose of 1mg/kg/d of dulapeptide and a dose of 200ug/kg/d of Ex9-39 by subcutaneous injection.Four weeks later,after ultrasonic measurements of LVDd,LVDs,and LVEF,the rats were sacrificed.Morphological changes of heart tissue observed by HE staining,Masson staining for collagen content,GLP-1R,SERCA2 a,PLB,p-PLB,PKG,Ca MKII,and p-Ry R were detected using Western blot.NT-pro BNP,c GMP,GLP-1,blood glucose and insulin were measured by Elisa.Results:(1)Blood glucose and insulin levels were not significantly different between the three groups.(2)HE staining showed that the degree of fibrosis in DOX group was more severe than that in N group,and Exendin9-39 could partially inhibit myocardial fibrosis.(3)Masson staining showed that CVF in DOX group [(5.88 ±0.13)%] was significantly higher than that in N group.After treatment with Dura glycopeptide,CVF in GLP-1RA group was lower than that in DOX group,and exendin9-39 antagonized the protective effect of Dura glycopeptide(all P < 0 05).(4)Western blot results showed that the levels of GLP-1R,PKG,SERCA2 a and p-PLB in DOX group were lower than those in N group,while the levels of PLB,p-RYR and Ca MKII were higher in Dulapeptide group After treatment with Dulapeptide,the levels of GLP-1R,PKG,SERCA2 a and p-PLB were increased,and the levels of PLB,p-RYR and Ca MKII were decreased.Exendin9-39 antagonized part of the effect of Dulapeptide.(5)The results of Elisa showed that compared with N group,c GMP and GLP-1 decreased in DOX group,c GMP and GLP-1 increased in GLP-1RA group,and c GMP and GLP-1 decreased partly in exendin9-39 group.(6)The results of echocardiography and NT-pro BNP showed that the values of LVDs and LVDD in DOX group were significantly higher than those in N group,while the values of LVEF in Dulapeptide group were lower than those in N group.After treatment with Dulapeptide,LVDs and LVDd decreased,while LVEF increased.Exendin9-39 inhibited the protective effect of Dulapeptide.Compared with N group,NT-pro BNP in DOX group increased significantly,NT-pro BNP decreased after treatment with dulapeptide,but exendin9-39 partially counteracted the protective effect of dulapeptide.Conclusion: In this study,the following conclusions were obtained after the establishment of rat myocardial fibrosis model using adriamycin and the intervention with GLP-1RA:(1)GLP-1RA can improve doxorubicin-induced myocardial fibrosis and ventricular hypertrophy and reverse myocardial remodeling;(2)The reversal of myocardial remodeling by GLP-1RA may be related to c GMP-PKG pathway.