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Rosuvastatin protects isolated hearts against ischemia-reperfusion injury: role of Akt-GSK-3β, metabolic environment, and mitochondrial permeability transition pore

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Abstract

The cardioprotective activity of rosuvastatin (R) is yet to be known. The objective of this study was to research whether R perfusion before global ischemia can mitigate myocardial ischemia-reperfusion damage, considering the metabolic condition in which these effects occur, and to contemplate potential mitochondrial benefits. Protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore (MPTP) are key elements in myocardial injury produced by ischemia-reperfusion. Isolated rat hearts were subjected to 25-min ischemia and 1-h reperfusion in the presence or absence of R, with or without Wortmannin (W), a phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor. Akt and GSK-3β were measured by Western blot analysis; lactate, glycogen, and G6PDH were determined; and Ca2+-induced MPTP opening was evaluated using a spectrophotometric method. Contractility was assessed by left ventricular developed pressure (LVDP), and rate-pressure product (RPP), peak rate of contraction and peak rate of relaxation (± dP/dt), and left ventricular end-diastolic pressure (LVEDP) were determined. Tissue samples were extracted to evaluate mitochondrial damage by electron microscopy and to assess infarct size. Statistical analysis employed ANOVA (n = 6/per group). Myocardial infarct size was significantly reduced by R, which also improved cardiac function. MPTP opening was delayed to 300 μM CaCl2, while use of W resulted in MPTP opening at 200 μM CaCl2. Electron microscopy showed better mitochondrial preservation with R, which reduced lactic acid production, increased glycogen consumption and G6PDH activity, as well as phosphorylation of Akt and GSK-3β. R before ischemia is cardioprotective against ischemic and reperfusion damage, activating Akt and regulating GSK-3β negatively and attenuating the MPTP opening.

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Acknowledgments

The authors thank Roemmers for the donation of Rosuvastatin. We also express our gratitude to Federico Reznik for his invaluable support in this investigation.

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Authors and Affiliations

  1. Physiology Unit. Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 7th floor, C1113AAD, Ciudad de Buenos Aires, Argentina

    Debora E. Vélez, Victoria E. Mestre-Cordero, Romina Hermann, Juliana Perego, Sofia Harriet, María de las Mercedes Fernandez-Pazos, Julieta Mourglia & M. Gabriela Marina-Prendes

  2. IQUIMEFA-CONICET, Junin 956, 7th floor, C1113AAD, Ciudad de Buenos Aires, Argentina

    Debora E. Vélez, Victoria E. Mestre-Cordero, Romina Hermann & M. Gabriela Marina-Prendes

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  1. Debora E. Vélez
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Correspondence to Debora E. Vélez.

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Key points

Hearts subjected to ischemia-reperfusion treated with rosuvastatin:

• Improved post-ischemic functional recovery and decreased infarct size.

• Decreased lactic acid production and increased the activity of G6PDH.

• Preserved mitochondrial structure, increasing the capacity of ATP synthesis.

• Activated Akt and negatively regulated GSK-3β, attenuating opening of the MPTP.

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Vélez, D.E., Mestre-Cordero, V.E., Hermann, R. et al. Rosuvastatin protects isolated hearts against ischemia-reperfusion injury: role of Akt-GSK-3β, metabolic environment, and mitochondrial permeability transition pore. J Physiol Biochem 76, 85–98 (2020). https://doi.org/10.1007/s13105-019-00718-z

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  • DOI: https://doi.org/10.1007/s13105-019-00718-z

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