P3564Alogliptin, a DPP-4 inhibitor, alleviates atrial remodeling and improves mitochondrial function and biogenesis in diabetic rabbits

Abstract

Background: There is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation (AF). Dipeptidyl peptidase-4 (DPP- 4) inhibitors such as alogliptin are novel glucose-lowering agents for the treatment of type 2 diabetes mellitus (DM). Purpose: We aimed to investigate the potential role of mitochondrial function and DPP-4 inhibition in atrial remodeling in the setting of diabetes. Methods: Ninety rabbits were randomized into 3 groups as follows: Control group (CON, n=30), alloxan-induced diabetic group (DM, n=30) and alogliptintreated (12.5mg/kd/d for 8 weeks) diabetic group (DM-A, n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The concentrations of glucagon-like peptide-1, insulin, and inflammatory and oxidative stress markers in serum were measured. Electrophysiological properties of Langendorffperfused rabbit hearts were assessed. Mitochondrial morphology, mitochondrial respiratory function, membrane potential and ROS generation rate were assessed. The protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were measured by Western blot analysis. Results: DM rabbits exhibited left ventricular hypertrophy and left atrial dilation without obvious hemodynamic abnormalities, and all of these changes were attenuated by alogliptin. Compared with the control group, higher AF inducibility in the DM group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling regulated by APN/AMPK. Conclusion: DPP-4 inhibitors can prevent AF by reversing electrophysiological abnormalities, improving mitochondrial function and promoting mitochondrial biogenesis.