Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Abstract

BackgroundThere is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation. In this study, we explored whether alogliptin, a dipeptidyl peptidase‐4 inhibitor, can prevent mitochondrial dysfunction and atrial remodeling in a diabetic rabbit model.Methods and ResultsA total of 90 rabbits were randomized into 3 groups as follows: control group (n=30), alloxan‐induced diabetes mellitus group (n=30), and alogliptin‐treated (12.5 mg/kg per day for 8 weeks) diabetes mellitus group (n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The serum concentrations of glucagon‐like peptide‐1, insulin, and inflammatory and oxidative stress markers were measured. Electrophysiological properties of Langendorff‐perfused rabbit hearts were assessed. Mitochondrial morphology, respiratory function, membrane potential, and reactive oxygen species generation rate were assessed. The protein expression of transforming growth factor β1, nuclear factor κB p65, and mitochondrial biogenesis–related proteins were measured by Western blot analysis. Diabetic 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 atrial fibrillation inducibility in the diabetes mellitus group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial reactive oxygen species production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by peroxisome proliferator–activated receptor‐γ coactivator 1α/nuclear respiratory factor‐1/mitochondrial transcription factor A signaling regulated by adiponectin/AMP‐activated protein kinase.ConclusionsDipeptidyl peptidase‐4 inhibitors can prevent atrial fibrillation by reversing electrophysiological abnormalities, improving mitochondrial function, and promoting mitochondrial biogenesis.

Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress‐Mediated Atrial Remodeling in Alloxan‐Induced Diabetes Mellitus Rabbits

“…Zhang et al found that DPP-4 inhibitors decreased mitochondrial ROS production rate and ameliorate arrhythmic substrate in a DM rabbit model. 49 In another study, Zou et al illustrated that ranolazine inhibits oxidative stress and improves mitochondrial function in the atrium of acetylcholine-CaCl 2 -induced atrial fibrillation rats partly by increasing the expression of antioxidants such as GSH-Px and manganese superoxide dismutase to reduce ROS levels in mitochondria. 50 Furthermore, in a canine model subjected to atrial tachycardia pacing (ATP, 400 bpm) without atrioventricular block for 4 weeks leading to left ventricular dysfunction, Sakabe et al evaluated the dynamics of atrialtachycardia remodeling.…”

“…Allopurinol prevented hyperglycemia‐induced oxidative stress, cardiomyocyte hypertrophy and cardiac fibrosis and attenuated cardiac dysfunction,15 in which prevention of ROS‐induced oxidative stress and reduction of myocardial collagen formation may represent one of the major pathogenic mechanisms. Zhang et al found that DPP‐4 inhibitors decreased mitochondrial ROS production rate and ameliorate arrhythmic substrate in a DM rabbit model 49. In another study, Zou et al illustrated that ranolazine inhibits oxidative stress and improves mitochondrial function in the atrium of acetylcholine‐CaCl 2 –induced atrial fibrillation rats partly by increasing the expression of antioxidants such as GSH‐Px and manganese superoxide dismutase to reduce ROS levels in mitochondria 50.…”

Pharmacological Inhibition of Serine Proteases to Reduce Cardiac Inflammation and Fibrosis in Atrial Fibrillation

“…Block of PAR-1 signaling Oral anti-platelet agent Unknown DPP-4 inhibitors (Lendeckel, 2001;Tremblay, 2014;Wronkowitz, 2014;Gong et al, 2015;Yamamoto, 2015;Chang, 2017;Zhang, 2017;Igarashi, 2018) Sitagliptin, saxagliptin and other gliptins…”

Higher versus standard starting dose of insulin glargine 100 U/mL in overweight or obese Chinese patients with type 2 diabetes: Results of a multicentre, open‐label, randomized controlled trial (BEYOND VII)

“…The International Diabetes Management Practices Study reported that the median body mass index (BMI) of patients with T2D increased from 26 kg/m 2 to 29 kg/m 2 between 2005 and 2017, while the proportion of insulin‐treated patients who achieved the target HbA1c of <7% (53 mmol/mol) decreased from 28% to 16% over the same period, suggesting that achieving the glycaemic target is an additional challenge with increasing BMI. Overweight and obese patients currently form the majority of patients with T2D worldwide, and ~60% of patients with T2D in China have a BMI of ≥25 kg/m 2 , corresponding to ~69 million Chinese adults . However, no specific insulin dosing algorithm has been determined in this population.…”