Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey.
Departments of Histology-Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey.
Mol Cell Biochem. 2020 Jun;469(1-2):97-107. doi: 10.1007/s11010-020-03731-9. Epub 2020 Apr 16.
Ticagrelor, a PY-receptor inhibitor, and a non-thienopyridine agent are used to treat diabetic patients via its effects on off-target mechanisms. However, the exact sub-cellular mechanisms by which ticagrelor exerts those effects remains to be elucidated. Accordingly, the present study aimed to examine whether ticagrelor influences directly the cardiomyocytes function under insulin resistance through affecting mitochondria-sarco(endo)plasmic reticulum (SER) cross-talk. Therefore, we analyzed the function and ultrastructure of mitochondria and SER in insulin resistance-mimicked (50-μM palmitic acid for 24-h) H9c2 cardiomyocytes in the presence or absence of ticagrelor (1-µM for 24-h). We found that ticagrelor treatment significantly prevented depolarization of mitochondrial membrane potential and increases in reactive oxygen species with a marked increase in the ATP level in insulin-resistant H9c2 cells. Ticagrelor treatment also reversed the increases in the resting level of free Ca and mRNA level of PY receptors as well as preserved ER stress and apoptosis in insulin-resistant H9c2 cells. Furthermore, we determined marked repression with ticagrelor treatment in the increased number of autophagosomes and degeneration of mitochondrion, including swelling and loss of crista besides recoveries in enlargement and irregularity seen in SER in insulin-resistant H9c2 cells. Moreover, ticagrelor treatment could prevent the altered mRNA levels of Becklin-1 and type 1 equilibrative nucleoside transporter (ENT1), which are parallel to the preservation of ultrastructural ones. Our overall data demonstrated that ticagrelor can directly affect cardiomyocytes and provide marked protection against ER stress and dramatic induction of autophagosomes, and therefore, can alleviate the ER stress-induced oxidative stress increase and cell apoptosis during insulin resistance.
替格瑞洛是一种血小板 P2Y12 受体抑制剂，也是一种非噻吩吡啶类药物，通过非靶点机制用于治疗糖尿病患者。然而，替格瑞洛发挥这些作用的确切亚细胞机制仍有待阐明。因此，本研究旨在探讨替格瑞洛是否通过影响线粒体-肌浆网（SR）的相互作用来直接影响胰岛素抵抗下的心肌细胞功能。因此，我们分析了在存在或不存在替格瑞洛（1μM，24 小时）的情况下，胰岛素抵抗模拟（50μM 棕榈酸 24 小时）的 H9c2 心肌细胞中线粒体和 SR 的功能和超微结构。我们发现，替格瑞洛治疗可显著防止胰岛素抵抗的 H9c2 细胞中线粒体膜电位去极化和活性氧增加，并显著增加 ATP 水平。替格瑞洛治疗还可逆转胰岛素抵抗的 H9c2 细胞中静息游离 Ca 水平和 PY 受体 mRNA 水平的增加，并保持内质网应激和细胞凋亡。此外，我们确定替格瑞洛治疗可显著抑制胰岛素抵抗的 H9c2 细胞中自噬体数量增加和线粒体变性，包括肿胀和嵴丢失，以及 SR 扩大和不规则性恢复。此外，替格瑞洛治疗可防止 Beclin-1 和 1 型平衡核苷转运蛋白（ENT1）的 mRNA 水平改变，这与超微结构的保存平行。我们的综合数据表明，替格瑞洛可以直接影响心肌细胞，并提供显著的保护作用，防止内质网应激和自噬体的急剧诱导，从而减轻胰岛素抵抗期间内质网应激诱导的氧化应激增加和细胞凋亡。
