Journal Article

A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats

Durak, Aysegul, Olgar, Yusuf, Turan, Belma, Akkus, Erman, Tuncay, Erkan, Degirmenci, Sinan

2018

Overview

Background Metabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect. Methods A 28-week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures. Results DAPA-treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q–R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K + -channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis-1 as well as provided significant augmentation in cytosolic Ca 2+ -homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na + -currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart. Conclusions Overall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion–fission proteins, out of its glucose-lowering effect.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Action Potentials - drug effects / Angiology / Animals / Antidiabetics / Aorta / Arrhythmias, Cardiac - blood / Arrhythmias, Cardiac - etiology / Arrhythmias, Cardiac - physiopathology / Arrhythmias, Cardiac - prevention & control / Benzhydryl Compounds - pharmacology / Blood glucose / Blood Glucose - drug effects / Blood Glucose - metabolism / Blood pressure / Body weight / Calcium channels (voltage-gated) / Calcium homeostasis / Cardiology / Cardiomyocytes / Cardiovascular disease / Diabetes / Disease Models, Animal / Electrophysiology / Glucose / Glucosides - pharmacology / Heart function / Heart rate / Heart Rate - drug effects / Heart Ventricles - drug effects / Heart Ventricles - metabolism / Heart Ventricles - physiopathology / High carbohydrate diet / Homeostasis / Hyperglycemia / Insulin / Insulin - pharmacology / Insulin Resistance / Kinases / Male / Medicine / Medicine & Public Health / Membrane potential / Membrane Potential, Mitochondrial - drug effects / Metabolic syndrome / Metabolic Syndrome - blood / Metabolic Syndrome - complications / Metabolic Syndrome - drug therapy / Metabolic Syndrome - physiopathology / Mitochondria / Mitochondria, Heart - drug effects / Mitochondria, Heart - metabolism / Mitochondria, Heart - pathology / mRNA / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Obesity / Original Investigation / Overweight / Oxidative stress / Potassium channels (voltage-gated) / Potassium Channels, Voltage-Gated - drug effects / Potassium Channels, Voltage-Gated - metabolism / Rats, Wistar / Rodents / SGLT2 inhibitors / Sodium channels (voltage-gated) / Sodium-Glucose Transporter 2 - genetics / Sodium-Glucose Transporter 2 - metabolism / Sodium-Glucose Transporter 2 Inhibitors - pharmacology / Ventricle / Ventricular Function, Left - drug effects / Voltage / Voltage-Gated Sodium Channels - drug effects / Voltage-Gated Sodium Channels - metabolism