| Background Oxidative stress and inflammation represent major pathophysiological pathways between atrial fibrillation(AF)and diabetes mellitus(DM),and have been related to mitochondrial dysfunction.Besides cardiovascular protective effects in myocardial ischemia,alogliptin might play an important protective role in the development of AF.However,the underlying mechanisms have remained unclear.The aim of this study was to investigate whether alogliptin exerts protective effects on atrial remodeling in streptozotocin(STZ)-induced type 2 diabetic rats,as well as its potential effects on mitochondrial function.Methods Eight-week-old male Sprague-Dawley(SD)rats(n=90)were randomly divided into three groups: 1)Control group(Con);2)DM group and 3)alogliptin-treated DM group(DM+A,20mg/kg/d).SD rats treated with high-fat diet and low-dose STZ(30mg/kg)were used as an animal model of type 2 diabetes mellitus.Animals received vehicle or alogliptin by gastric gavage after successful modeling.After 8 weeks of alogliptin administration,rats were sacrificed for the following relevant experiments.Rat's body weight and fasting blood glucose concentration were monitored and recorded per week.Size of chambers of the heart,ventricular wall thickness and left ventricular ejection fraction(LVEF)were detected by echocardiography.Blood pressure,intraventricular pressure and ądp/dtmax were determined by invasive hemodynamic measurements.The sections from each atrial tissue were stained with hematoxylin-eosin(HE)or Masson's trichrome staining to evaluate the morphological changes of myocardial fibers and the extent of interstitial fibrosis,respectively.The levels of serum glucose,insulin,renal function,lipid,inflammation and oxidative stress-related indicators were measured by ELISA.Interatrial conduction times(IACT),atrial effective refractory period(AERP)and AF induction were tested using the Langendorff perfused heart.Activation maps,direction and velocity of conduction in the left and right atrium were recorded by epicardial activation mapping assessment.Mitochondrial respiration functionality was assessed by mitochondrial membrane potentials and respiratory control rate(RCR)examinations.The protein expressions of Mn-SOD,TGF-?1,BAX,Bcl-2,PGC-1?,NRF-1,Tfam,Mfn-1 and Drp-1 were evaluated by Western blot.Results1.Establishment of STZ-induced type 2 diabetes diabetic rat model: Compared with the Con group,the DM rats treated with high-fat diet and low-dose STZ had elevated blood glucose levels,demonstrating the successful diabetic rat model.Throughout the study period,rats in DM and DM+A groups had significantly elevated blood glucose levels compared to the Con group.The overall trend of body weight among the three groups increased,but no significant difference was noticed.At the end of the study period,the DM group demonstrated higher insulin level compared to the Con group.Alogliptin treatment reduced the level of insulin in DM rats.2.Changes in cardiac structure and function in each group: Compared with Con group,left atrial anteroposterior diameter,left ventricular posterior wall thickness and interventricular septal thickness were significantly increased in the DM group.Alogliptin treatment partially reduced the diameter of left atria and the thickness of ventricular wall in the pathologic state of DM.However,some conventional cardiac systolic and diastolic parameters,such as left ventricular end-diastolic pressure,LVEF,systolic blood pressure,diastolic blood pressure,and ądp/dtmax did not differ between the three groups.3.Changes in atrial structural remodeling in each group: Compared with the Con group,distinctly disordered layout of atrial myocytes,extensive interstitial fibrosis,more broadened interstitial space among the atrial myofibers,as well as larger collagen volume fraction were observed in the DM group.These alterations were attenuated by treatment with alogliptin.4.Changes in serum biomarkers in each group: The results indicate that the levels of triglycerides,total cholesterol,LDL-c,hs-CRP and MDA were higher,while the antioxidant enzyme SOD decreased significantly in the untreated DM group compared to the Con group.Except for triglycerides and LDL-c,there were significant effects of alogliptin on the total cholesterol,hs-CRP,MDA and SOD levels in the DM+A rats.Creatinine,BUN and HDL-c were not significantly different between the three groups.5.Changes in the atrial electrical remodeling in each group: Electrophysiology data indicated that IACT and AERP values from the right and left atrium tended to increase in the DM group compared with the Con group,but no statistically significant difference was evident.AF inducibility was significantly increased in the DM.Compared with the Con group,atrial activation mapping revealed a more heterogeneous and significantly disordered conduction,and the decreased conduction velocity in DM rats under conditions of spontaneous sinus beating.These changes were significantly attenuated by alogliptin treatment.6.Changes in mitochondrial function in each group: Compared with the Con group,state 3 respiration rate was significantly decreased while state 4 respiration rate had a declining trend in the DM group,corresponding to the lower respiratory control ratio.In addition,evidence for mitochondrial membrane potential revealed decreased significantly in DM rats compared with the Con group.The treatment of alogliptin attenuated these changes.7.Changes in protein expressions in each group: Compared to the Con group,the increased protein levels of TGF-?1,BAX and Drp-1 and the decreased levels of Bcl-2,PGC-1?,NRF-1,Tfam and Mfn-1 were observed in the DM group.No significant difference in the protein expression of Mn-SOD was observed among the study groups.Alogliptin effectively attenuated these protein expression alterations.Conclusion Alogliptin attenuated atrial structural and electrical remodeling,and improved mitochondrial dysfunction induced by DM.Thus,dipeptidyl peptidase-4 inhibition by alogliptin could be a promising option for the management of AF in the setting of DM. |
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