Journal Article

Alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function in diabetic rabbits

Yang, Yajuan, Tse, Gary, Zhang, Zhiwei, Zhang, Xiaowei, Suo, Ya, Liu, Changle, Liu, Tong, Qiu, Jiuchun, Zhao, Yungang, Li, Guangping, Jiang, Ning, Liu, Ruimeng

2018

Overview

Background There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. Methods A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-β1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. Results DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e′ ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (− dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway. Conclusions The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Angiology / Animal control / Animals / Apoptosis / Biosynthesis / Blood pressure / Cardiology / Cardiomyopathy / Depolarization / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - drug therapy / Diabetes Mellitus, Experimental - metabolism / Diabetic Cardiomyopathies - etiology / Diabetic Cardiomyopathies - metabolism / Diabetic Cardiomyopathies - physiopathology / Diabetic Cardiomyopathies - prevention & control / Diabetic cardiomyopathy / Diastole - drug effects / Dipeptidyl peptidase-4 inhibitors / Dipeptidyl-Peptidase IV Inhibitors - pharmacology / Electron transport / Fasting / Fibrosis / Glucagon / Glucagon-like peptide 1 / Glucose / Heart failure / Hypertrophy / Hypertrophy, Left Ventricular - etiology / Hypertrophy, Left Ventricular - metabolism / Hypertrophy, Left Ventricular - physiopathology / Hypertrophy, Left Ventricular - prevention & control / Inflammation / Insulin / Medicine / Medicine & Public Health / Membrane potential / Membrane Potential, Mitochondrial - drug effects / Mitochondria / Mitochondria, Heart - drug effects / Mitochondria, Heart - metabolism / Mitochondria, Heart - pathology / Mitochondrial biogenesis / Mitochondrial function / Myocardium / NF-κB protein / Nuclear Respiratory Factor 1 - metabolism / Original Investigation / Oxidative stress / Oxidative Stress - drug effects / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism / Piperidines - pharmacology / Rabbits / Reactive oxygen species / Reactive Oxygen Species - metabolism / Signal transduction / Signal Transduction - drug effects / Stroke Volume - drug effects / Structure-function relationships / Transcription Factors - metabolism / Transforming growth factor-b1 / Uracil - analogs & derivatives / Uracil - pharmacology / Ventricle / Ventricular Dysfunction, Left - etiology / Ventricular Dysfunction, Left - metabolism / Ventricular Dysfunction, Left - physiopathology / Ventricular Dysfunction, Left - prevention & control / Ventricular Function, Left - drug effects / Ventricular Pressure - drug effects / Ventricular Remodeling - drug effects / Western blotting