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

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Abstract

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.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by Grants (No. SBAG-216S979) from The Scientific and Technological Research Council of Turkey.

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  1. Yusuf Olgar and Erkan: equal first authors.

  2. Semir Ozdemir and Belma Turan: equal senior authors.

Authors and Affiliations

  1. Departments of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey

    Yusuf Olgar, Erkan Tuncay, Aysegul Durak & Belma Turan

  2. Departments of Histology-Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey

    Deniz Billur

  3. Departments of Biophysics, Faculty of Medicine, Akdeniz University, Antalya, Turkey

    Semir Ozdemir

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  1. Yusuf Olgar
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Contributions

BT designed and supervised the research and provided the final approval of the version to be published; SO supervised the research and contributed to the editing of the manuscript; YO, AD, and ET contributed and performed the experiments and analyzed the data; DB performed all electron microscopy analysis. All authors discussed the results and commented on the manuscript. It is certified that there was no data manipulation or data from papers published in other journals are included. Furthermore, appropriate precautions have been taken to maintain high ethical standards. All authors have read the manuscript and authorized the submission for publication.

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Correspondence to Semir Ozdemir or Belma Turan.

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Olgar, Y., Tuncay, E., Billur, D. et al. Ticagrelor reverses the mitochondrial dysfunction through preventing accumulated autophagosomes-dependent apoptosis and ER stress in insulin-resistant H9c2 myocytes. Mol Cell Biochem 469, 97–107 (2020). https://doi.org/10.1007/s11010-020-03731-9

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