Study On The Mechanism Of Protective Effect Of Dagliflozin In Rats With Heart Failure

OBJECTIVE: To explore the relationship between interleukin-35(IL-35),signal transducer and activator of transcription(STAT3)and doxorubicin hydrochloride induced heart failure in rats.We investigated whether the myocardial protective effect of sodium-dependent glucose transporters-2 inhibitor(SGLT-2i)was related to the IL-35/STAT3 pathway in rats.METHODS: Forty healthy 8-10 week old male Wistar rats were firstly selected and then randomly grouped.Ejection fraction(EF)and left ventricular shortening(LVFS)were measured by cardiac ultrasound,and N-terminal pro-B type natriuretic peptide(NTP)was measured by ELISA.The levels of pro-B type natriuretic peptide(NT-pro BNP),IL-35 and STAT3 were measured by ELISA to assess whether the heart failure model was established.After treatment,NT-pro BNP,IL-35 and STAT3 were measured in all rats,and IL-35,p-STAT3 and t-STAT3 were measured by western blot.The extent of fibrosis and myocardial cell arrangement were compared between the groups.The correlation between the protective effect of dagliflozin on myocardial tissue and the IL-35/STAT3 pathway was investigated.RESULTS: Doxorubicin hydrochloride by intraperitoneal injection could cause heart failure in rats.LVEF was reduced and NT-Pro BNP was increased in rats after heart failure.There was also a decrease in IL-35,with a statistically significant difference(P<0.05).After treatment with SGLT-2i,the ejection fraction increased,NT-Pro BNP decreased and IL-35 concentrations increased,with a statistically significant difference(P<0.05),suggesting that a decrease in IL-35 is associated with the development of heart failure.The expression of IL-35 and STAT3 in myocardial tissue was reduced after heart failure,and the expression of IL-35 and STAT3 increased after SGLT-2i administration,suggesting that SGLT-2i can achieve myocardial protection by upregulating IL-35 and STAT3 expression.CONCLUSIONS: 1.6 weeks after intraperitoneal injection of doxorubicin hydrochloride,rats in the heart failure group showed decreased LVEF,LVFS,IL-35 and increased NTpro BNP,suggesting the establishment of a heart failure model,and IL-35 concentration was positively correlated with LVEF.2.28 days after dagliflozin gavage treatment,rats in the treatment group showed increased LVEF,LVFS,IL-35 and decreased NT-pro BNP compared with rats in the control group.3.HE staining of pathological sections showed that myocardial cells in the heart failure group were disorganized compared with those in the blank group,and the changes in the treated group were milder than those in the control group;Masson staining showed that the rats in the heart failure group showed myocardial fibrosis and increased collagen volume fraction compared with the blank group,while the collagen volume fraction in the treated group was lower than that in the blank group,suggesting that dagliflozin has a therapeutic effect on heart failure.4.Immunoblotting showed that the expression of IL-35 and STAT3 in myocardial cells of both treated and control rats were downregulated,but the expression of SGLT-2i was higher in the treated group than in the control group.It is suggested that SGLT-2i may protect myocardium by up-regulating IL-35 and STAT3 expression.