| Objective: In recent years,the incidence of type 2 diabetes has increased significantly and the mortality caused by diabetic cardiomyopathy is increased.More studies have confirmed that diabetic cardiomyopathy is associated with impaired mitochondrial function.Studies have shown that sodium-glucose co-transporters 2(SGLT-2)inhibitors can reduce cardiovascular mortality in patients with type 2 diabetes,however the mechanism remains unclear.In this study,we investigated the effect of the SGLT-2 inhibitor,empagliflozin on ventricular remodeling and mitochondrial function in type 2 diabetic rats,and whether it could delay the occurrence of diabetic cardiomyopathy.Methods: There were 64 adult male SD rats.16 rats were randomly selected as the control group and given normal diet,and the other 48 rats were fed with high-fat diet for 4 weeks.Then,a small dose of one-time tail intravenous injection of streptozocin(STZ,30mg/kg)was given to experimental high-fat diet rats.After 1 week,tail venous blood was taken to measure blood glucose,and the random blood glucose > 16.7mmol/L was used as the model of type 2 diabetes.After the successful establishment of the type 2 diabetes model,the rats were randomly divided into three groups: diabetes mellitus group(D group),low dose empagliflozin group(low-EMPA,10mg/kg/d)and high does empagliflozin group(high-EMPA,30mg/kg/d),with 16 rats in each group.Body weight and blood glucose were measured weekly in all experimental rats.After 8 weeks of empagliflozin intervention,8 animals in each group were randomly selected for mitochondrial function related experiments,and the remaining 8 were used for echocardiography,hemodynamics,enzyme-linked immunosorbent assay(ELISA),pathology and molecular biology experiments.Results:1.Blood glucose level and body weight were significantly increased in the D group after modeling.The body weight of the low-EMPA and high-EMPA groups was peaked at the fourth week,and then decreased.In addition,triglyceride and total cholestenone were both increased in the D group,while decreased after empagliflozin treatment;2.Compared to the C group,LAD,IVST and LVPWT were significantly higher,while the E/A value was lower in the D group.The above indicators showed improvement after empagliflozin treatment(P < 0.05);3.Compared to the C group,SBP,DBP,MBP and-dp/dtmax were increased,while +dp/dtmax was decreased in the D group.SBP,DBP,MBP and-dp/dtmax showed a downward trend,while +dp/dtmax showed an upward trend after 8 weeks of empagliflozin treatment(P > 0.05);4.Compared to the C group,myocardial cross-sectional area and collagen volume fraction were increased in the D group(P < 0.05),while the pathological changes were significantly inhibited after high dose empagliflozin treatment(P < 0.05);5.Compared to the C group,serum SOD activity,protein levels of Mn-SOD and CS were significantly lower,while serum hs-CRP,MDA levels and TGF-β1 protein expression level were significantly higher in the D group,and the improvement was observed in the high-EMPA group(P < 0.05);6.Compared to the C group,RCR value and Δ Ψ m were significantly lower in the D group(P < 0.05),and two groups of empagliflozin improved mitochondrial function(P < 0.05);7.Compared to the C group,the expression levels of mitochondrial biosynthesis related proteins(Sirt-1/PGC-1a/NRF-1/Tfam)were lower in the D group.Compared to the D group,the expression levels of these proteins were up-regulated in the highEMPA group.Mitochondrial fusion proteins Mfn-1,OPA-1 were down-regulated and mitochondrial fission protein Drp-1 was up-regulated in the D group,and the expression levels of above proteins were improved after empagliflozin treatment.Conclusion: Empagliflozin,a SGLT-2 inhibitor improves ventricular remodeling in type 2 diabetes mellitus.The mechanism involves inhibiting inflammation,alleviating oxidative stress,improving mitochondrial respiratory function,restoring the membrane potential,regulating mitochondrial dynamics and promoting mitochondrial biosynthesis. |
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