Durak Aysegul, Akkus Erman, Canpolat Asena Gokcay, Tuncay Erkan, Corapcioglu Demet, Turan Belma
Faculty of Medicine, Department of Biophysics, Ankara University, Ankara, Turkey.
Faculty of Medicine, Department of Internal Medicine, Ankara University, Ankara, Turkey.
Clin Exp Pharmacol Physiol. 2022 Jan;49(1):46-59. doi: 10.1111/1440-1681.13590. Epub 2021 Oct 27.
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 Ca -level, which are confirmed with a full recovery in activated Na /Ca -exchanger currents (I ). 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 2α. 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, Ca -homeostasis, and mitochondrial dysfunction in ventricular cardiomyocytes.
胰高血糖素样肽-1受体（GLP-1R）激动剂对心脏的多效性作用在肥胖或糖尿病患者中已得到认可。然而，关于这些激动剂在代谢紊乱情况下心脏保护作用的分子机制却知之甚少。我们评估了GLP-1R激动剂利拉鲁肽治疗对高碳水化合物诱导的代谢综合征大鼠（MetS大鼠）左心室心肌细胞的影响，这些大鼠的特征为胰岛素抵抗和伴有长QT的心脏功能障碍。利拉鲁肽（0.3mg/kg，持续4周）治疗MetS大鼠可显著逆转长QT，其机制是缩短延长的动作电位持续时间并恢复受抑制的钾电流。我们还确定渗漏的肌浆网（SR）和高细胞溶质钙水平有显著恢复，这通过激活的钠/钙交换电流（I）的完全恢复得到证实。此外，利拉鲁肽治疗可显著逆转去极化的线粒体膜电位（MMP），增加氧化标志物的产生以及细胞酸化，并伴有ATP产生减少。我们对分离的心肌细胞进行的光学显微镜分析显示，利拉鲁肽治疗的MetS组有明显恢复，如高度扩张的T小管和SR-线粒体连接明显逆转。此外，我们确定利拉鲁肽治疗的MetS组中降低的葡萄糖转运蛋白4（GLUT4）蛋白水平有显著增加，这可能与酪蛋白激酶2α的恢复有关。总体而言，该研究证明了利拉鲁肽在MetS大鼠中诱导心脏保护的分子机制，至多是通过其多效性作用，如缓解心室心肌细胞的电异常、钙稳态和线粒体功能障碍。
