Cardiovascular diabetology, 2018-11, Vol.17 (1), p.144-144, Article 144
2018
Details
- Autor(en) / Beteiligte
- Titel
- A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats
- Ist Teil von
- Cardiovascular diabetology, 2018-11, Vol.17 (1), p.144-144, Article 144
- Ort / Verlag
- England: BioMed Central
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- SpringerLink (Online service)
- Beschreibungen/Notizen
- 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. 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. 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 -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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1475-2840eISSN: 1475-2840DOI: 10.1186/s12933-018-0790-0Titel-ID: cdi_doaj_primary_oai_doaj_org_article_a36d75df9c104ae59489b6cf4566cfd2
- Format
- –
- Schlagworte
- Action Potentials - drug effects, Adenosine diphosphate, 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, Calcium ions, Carbohydrates, 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, Membrane potential, Membrane Potential, Mitochondrial - drug effects, Metabolic disorders, 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, Oxidation, Oxidative stress, Potassium channels (voltage-gated), Potassium Channels, Voltage-Gated - drug effects, Potassium Channels, Voltage-Gated - metabolism, Proteins, Rats, Rats, Wistar, Risk factors, 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