Glucagon-like peptide-1 receptor agonist treatment of high carbohydrate intake-induced metabolic syndrome provides pleiotropic effects on cardiac dysfunction through alleviations in electrical and intracellular Ca2+ abnormalities and mitochondrial dysfunction


Durak A., Akkuş E., Gökçay Canpolat A., Tuncay E., Çorapçıoğlu D., Turan B.

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, cilt.49, ss.46-59, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 49
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1111/1440-1681.13590
  • Dergi Adı: CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Agricultural & Environmental Science Database, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, SportDiscus, Veterinary Science Database
  • Sayfa Sayıları: ss.46-59
  • Anahtar Kelimeler: arrhythmia, electrical activity, insulin resistance, ion-homeostasis, sodium-calcium exchanger, LEFT-VENTRICULAR FUNCTION, HEART-FAILURE, RYANODINE RECEPTOR, OXIDATIVE STRESS, PKA PHOSPHORYLATION, NATRIURETIC-PEPTIDE, GLP-1 RECEPTOR, GLUCOSE-UPTAKE, LIRAGLUTIDE, CALCIUM
  • Ankara Üniversitesi Adresli: Evet

Özet

The pleiotropic effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on the heart have been recognised in obese or diabetic patients. However, little is known regarding the molecular mechanisms of these agonists in cardioprotective actions under metabolic disturbances. We evaluated the effects of GLP-1R agonist liraglutide treatment on left ventricular cardiomyocytes from high-carbohydrate induced metabolic syndrome rats (MetS rats), characterised with insulin resistance and cardiac dysfunction with a long-QT. Liraglutide (0.3 mg/kg for 4 weeks) treatment of MetS rats significantly reversed long-QT, through a shortening the prolonged action potential duration and recovering inhibited K+-currents. We also determined a significant recovery in the leaky sarcoplasmic reticulum (SR) and high cytosolic Ca2+-level, which are confirmed with a full recovery in activated Na+/Ca2+-exchanger currents (I-NCX). Moreover, the liraglutide treatment significantly reversed the depolarised mitochondrial membrane potential (MMP), increased production of oxidant markers, and cellular acidification together with the depressed ATP production. Our light microscopy analysis of isolated cardiomyocytes showed marked recoveries in the liraglutide-treated MetS group such as marked reverses in highly dilated T-tubules and SR-mitochondria junctions. Moreover, we determined a significant increase in depressed GLUT4 protein level in liraglutide-treated MetS group, possibly associated with recovery in casein kinase 2 alpha. Overall, the study demonstrated a molecular mechanism of liraglutide-induced cardioprotection in MetS rats, at most, via its pleiotropic effects, such as alleviation in the electrical abnormalities, Ca2+-homeostasis, and mitochondrial dysfunction in ventricular cardiomyocytes.