Alogliptin,a DPP-4 Inhibitor,Alleviates Atrial Remodeling And Improves Mitochondrial Function And Biogenesis In Diabetic Rabbits

Objective: Diabetes mellitus(DM)is the independent risk factor of atrial fibrillation(AF).However,its pathogenesis is still unclear.Emerging evidences showed that the disorder of energy metabolism and mitochondrial dysfunction are involved in the pathophysiological process of AF.Dipeptidyl peptidase-4(DPP-4)inhibitors have been showed that they can improve the function of mitochondria.In this study,we design to investigate the effect of alogliptin,a DPP-4 inhibitor,on atrial mitochondrial remodeling and metabolic stress related AF.Methods: Healthy Japanese white rabbits were used to establish the model of DM,and were randomly divided into three groups: Control group(C group),injected with saline of 4 ml via ear vein;DM group(D group),injected with alloxan of 120mg/kg;DM+alogliptin group(DA group),treated with alogliptin of 12.5mg/kg/d.30 rabbits in each group were feeded for 8 weeks.Then 10 rabbits were randomly selected from each group for the following researches: 1.Echocardiographic and hemodynamic examinations were performed,and serum insulin(INS),glucagon like peptide-1(GLP-1),and inflammatory and oxidative markers including hs-CRP,MDA and 8-OHDG were measured.HE and Masson staining were used to evaluate the cross-sectional area of atrial myocytes and atrial interstitial fibrosis respectively.The protein expression of TGF-β1、NF-κBp65,mitochondrial biogenesis and dynamics related proteins were evaluated by Western bloting.RT-PCR was used to evaluate the m RNA expression of PGC-1α/NRF-1/Tfam and the subunits of Complex Ⅰ-Ⅴ.2.Isolated rabbit hearts were Langendorff perfused.Atrial refractory effective period(AERP),atrial AERP dispersion(AERPD),interatrial conduction time(IACT)and vulnerability to AF were assessed.3.Mitochondrial respiratory rate control(RCR),membrane potential(Δψ)and ROS generation rate were assessed.Results: 1.Compared with the C group,the left atrial diameter(LAD),interventricular septal(IVS)and left ventricular posterior wall(LVPW)were increased in both D and DA group(P < 0.01).However,in DA group,they were decreased compared with the D group.No difference was observed in left ventricular ejection fraction(LVEF)and the hemodynamic parameters.2.In comparison with C group,the level of INS(8.01±1.66 mmol/L vs.17.36±3.35 mmol/L,P<0.01)and GLP-1(0.35±0.07 pmol/L vs.1.21±0.38 pmol/L,P<0.01)in D group were decreased,while alogliptin treatment increased the level of GLP-1(0.80±0.19 pmol/L vs.0.35±0.07 pmol/L,P<0.01).3.There were increased MDA,8-OHDG and hs-CRP concentrations(P < 0.01)and decreased SOD activity(P < 0.05)in D group compared with C group(P < 0.01),which were attenuated by alogliptin treatment(P < 0.01).4.Compared with C group,atrial cardiomyocytes and collagen volume fraction in D group were increased(P<0.05),and were attenuated by the treatment of alogliptin(P<0.05).5.In electrophysiologic study,AERPD in D group was longer than in C group and DA group(P<0.01).And also,IACT at basic cycle length of 150 ms,200ms and 250 ms in D group were longer than in C and DA group(P<0.01).DM resulted in an increased AF induction rate from 1.33% to 5.56%,while alogliptin treatment decreased it from 5.56% to 2.44%.6.The D group showed a lower RCR values and Δψ than the other two groups(P < 0.05),and alogliption treatment reversed this decrease(P < 0.05 or 0.01).On the contrary,the D group presented markedly higher mitochondrial ROS generation rate than the C group,and alogliptin treatment significantly suppressed it(P < 0.01).7.Western blot study showed that TGF-β1 and NF-κBp65 in D group were higher than the other two groups.Mitochondrial biogenesis and dynamic protein related proteins,including APN,p AMPK,PGC-1α,NRF1,Tfam,Drp1,Mfn1 and OPA1 were down regulated in the D group,but they were attenuate by the treatment of alogliption.However,the levels of AMPK and ATP5 A showed no statistical difference.8.The m RNA levels of PGC-1α and Tfam were lower than the other two groups,but NRF1 was shown no significant difference.Conclusion: DPP-4 inhibitors ameliorate atrium substrate,and may be useful for the prevention of AF in patients with DM.The mechanism may refer to alleviating mitochondrial oxidative stress,improving mitochondrial respiration function and promoting mitochondrial biogenesis.