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

Cardiovasc Diabetol. 2018 Nov 17;17(1):144. doi: 10.1186/s12933-018-0790-0.

Abstract

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 Ca2+-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.

Keywords: Diabetes; Electrophysiology; Heart function; Insulin resistance; Oxidative stress; SGLT2 inhibitors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Arrhythmias, Cardiac / blood
  • Arrhythmias, Cardiac / etiology
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Benzhydryl Compounds / pharmacology*
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Disease Models, Animal
  • Glucosides / pharmacology*
  • Heart Rate / drug effects*
  • Heart Ventricles / drug effects*
  • Heart Ventricles / metabolism
  • Heart Ventricles / physiopathology
  • Insulin / pharmacology
  • Insulin Resistance*
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Metabolic Syndrome / blood
  • Metabolic Syndrome / complications
  • Metabolic Syndrome / drug therapy*
  • Metabolic Syndrome / physiopathology
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Mitochondria, Heart / pathology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Potassium Channels, Voltage-Gated / drug effects
  • Potassium Channels, Voltage-Gated / metabolism
  • Rats, Wistar
  • Sodium-Glucose Transporter 2 / genetics
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors / pharmacology*
  • Ventricular Function, Left / drug effects
  • Voltage-Gated Sodium Channels / drug effects
  • Voltage-Gated Sodium Channels / metabolism

Substances

  • Benzhydryl Compounds
  • Blood Glucose
  • Glucosides
  • Insulin
  • Potassium Channels, Voltage-Gated
  • Slc5a2 protein, rat
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Voltage-Gated Sodium Channels
  • dapagliflozin