Vol.:(0123456789) 1 3 Molecular and Cellular Biochemistry https://doi.org/10.1007/s11010-020-03731-9 Ticagrelor reverses the mitochondrial dysfunction through preventing accumulated autophagosomes‑dependent apoptosis and ER stress in insulin‑resistant H9c2 myocytes Yusuf Olgar 1  · Erkan Tuncay 1  · Deniz Billur 2  · Aysegul Durak 1  · Semir Ozdemir 3  · Belma Turan 1 Received: 24 January 2020 / Accepted: 7 April 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Ticagrelor, a P 2 Y 12 -receptor inhibitor, and a non-thienopyridine agent are used to treat diabetic patients via its efects on of-target mechanisms. However, the exact sub-cellular mechanisms by which ticagrelor exerts those efects remains to be elucidated. Accordingly, the present study aimed to examine whether ticagrelor infuences directly the cardiomyocytes func- tion under insulin resistance through afecting 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 signifcantly 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 2+ and mRNA level of P 2 Y 12 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 Beck- lin-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 afect 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. Keywords P2Y12 receptors · Insulin resistance · Heart function · Mitochondria · ATP · ROS Introduction Both hyperglycemia and insulin resistance are important fac- tors to underline the tissue and cellular metabolic disorders. Those are also accepted as initiators of organ dysfunction, including cardiac dysfunction [1–3]. Although previous reports emphasized the association between heart failure and generalized insulin resistance [3–6] there are contro- versies related to these considerations [7–9]. The changes in metabolism and signaling pathways including insulin signal- ing pathways or glucose transport in the heart impair cardiac metabolism, structure, and function while further leading to adverse remodeling in the heart [10, 11]. Therefore, with consideration of the complexity of insulin signaling within the myocardium, the new therapeutic approaches will be important to treat or prevent any type of heart failure under insulin resistance. Yusuf Olgar and Erkan: equal frst authors. Semir Ozdemir and Belma Turan: equal senior authors. * Semir Ozdemir osemir@akdeniz.edu.tr * Belma Turan belma.turan@medicine.ankara.edu.tr 1 Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey 2 Departments of Histology-Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey 3 Departments of Biophysics, Faculty of Medicine, Akdeniz University, Antalya, Turkey