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Ticagrelor alleviates high-carbohydrate intake induced altered electrical activity of ventricular cardiomyocytes by regulating sarcoplasmic reticulum–mitochondria miscommunication

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Abstract

Metabolic syndrome (MetS) is associated with additional cardiovascular risk in mammalians while there are relationships between hyperglycemia-associated cardiovascular dysfunction and increased platelet P2Y12 receptor activation. Although P2Y12 receptor antagonist ticagrelor (Tica) plays roles in reduction of cardiovascular events, its beneficial mechanism remains poorly understood. Therefore, we aimed to clarify whether Tica can exert a direct protective effect in ventricular cardiomyocytes from high-carbohydrate diet-induced MetS rats, at least, through affecting sarcoplasmic reticulum (SR)–mitochondria (Mit) miscommunication. Tica treatment of MetS rats (150 mg/kg/day for 15 days) significantly reversed the altered parameters of action potentials by reversing sarcolemmal ionic currents carried by voltage-dependent Na+ and K+ channels, and Na+/Ca2+-exchanger in the cells, expressed P2Y12 receptors. The increased basal-cytosolic Ca2+ level and depressed SR Ca2+ load were also reversed in Tica-treated cells, at most, though recoveries in the phosphorylation levels of ryanodine receptors and phospholamban. Moreover, there were marked recoveries in Mit structure and function (including increases in both autophagosomes and fragmentations) together with recoveries in Mit proteins and the factors associated with Ca2+ transfer between SR–Mit. There were further significant recoveries in markers of both ER stress and oxidative stress. Taken into consideration the Tica-induced prevention of ER stress and mitochondrial dysfunction, our data provided an important document on the pleiotropic effects of Tica in the electrical activity of the cardiomyocytes from MetS rats. This protective effect seems through recoveries in SR–Mit miscommunication besides modulation of different sarcolemmal ion-channel activities, independent of P2Y12 receptor antagonism.

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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. SBAG216S979) from The Scientific and Technological Research Council of Turkey.

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Authors and Affiliations

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

    Yusuf Olgar, Aysegul Durak, Sinan Degirmenci, Erkan Tuncay & Belma Turan

  2. Faculty of Medicine, Department of Histology and Embryology, Ankara University, Ankara, Turkey

    Deniz Billur

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

    Semir Ozdemir

  4. Faculty of Medicine, Department of Biophysics, Lokman Hekim University, Ankara, Turkey

    Belma Turan

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  1. Yusuf Olgar
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B.T. designed and supervised the research and provided the final approval of the version to be published; S.O. supervised the research and contributed to the editing of the manuscript; Y.O., E.T., A.D, and S.D. contributed and performed the experiments and analyzed the data; D.B. performed all light and electron microscopic analysis. All authors discussed the results and commented on the manuscript.

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Correspondence to Semir Ozdemir or Belma Turan.

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All experimental protocols were approved by the Institutional Animal Care and Use Committee of the Ankara University. All animals received human care under an institutionally approved experimental animal protocol with ethical license in Turkey.

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Olgar, Y., Durak, A., Degirmenci, S. et al. Ticagrelor alleviates high-carbohydrate intake induced altered electrical activity of ventricular cardiomyocytes by regulating sarcoplasmic reticulum–mitochondria miscommunication. Mol Cell Biochem 476, 3827–3844 (2021). https://doi.org/10.1007/s11010-021-04205-2

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