Ticagrelor reverses the mitochondrial dysfunction through preventing accumulated autophagosomes-dependent apoptosis and ER stress in insulin-resistant H9c2 myocytes


OLĞAR Y., TUNCAY E., BİLLUR D., DURAK A., ÖZDEMİR S., TURAN B.

Molecular and Cellular Biochemistry, vol.469, no.1-2, pp.97-107, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 469 Issue: 1-2
  • Publication Date: 2020
  • Doi Number: 10.1007/s11010-020-03731-9
  • Journal Name: Molecular and Cellular Biochemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Agricultural & Environmental Science Database, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.97-107
  • Keywords: Insulin resistance, Heart function, Mitochondria, ATP, ROS, ACUTE CORONARY SYNDROMES, P2Y(12) RECEPTOR, NUCLEOSIDE TRANSPORTER, HEART-FAILURE, VENTRICULAR-FIBRILLATION, PLATELET INHIBITION, MORTALITY, MUSCLE, CONTRACTILITY, ACTIVATION
  • Lokman Hekim University Affiliated: No

Abstract

© 2020, Springer Science+Business Media, LLC, part of Springer Nature.Ticagrelor, a P2Y12-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 Ca2+ and mRNA level of P2Y12 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.