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Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress

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Abstract

Ischemia impairs the adenine nucleotide translocase (ANT), which transports ADP and ATP across the inner mitochondrial membrane. We investigated whether ANT1 overexpression has protective effects on ischemic hearts. Myocardial infarction was induced in wild-type (WT) and heart-specific ANT1-transgenic (ANT1-TG) rats, and hypoxia was set in isolated cardiomyocytes. ANT1 overexpression reduced the myocardial infarct area and increased the survival rate of infarcted rats. Reduced ANT1 expression and increased 4-hydroxynonenal modification of ANT paralleled to impaired ANT function in infarcted WT hearts. ANT1 overexpression improved ANT expression and function. This was accompanied by reduced mitochondrial cytochrome C release and caspase-3 activation. ANT1-TG hearts suffered less from oxidative stress, as shown by lower protein carbonylation and 4-hydroxynonenal modification of ANT. ANT1 overexpression also increased cell survival of hypoxic cardiomyocytes and attenuated reactive oxygen species (ROS) production. This was linked to higher stability of mitochondrial membrane potential and lower activity of ROS detoxifying catalase. ANT1-TG cardiomyocytes also showed higher resistance against H2O2 treatment, which was independent of catalase activity. In conclusion, ANT1 overexpression compensates impaired ANT activity under oxygen-restricted conditions. It reduces ROS production and oxidative stress, stabilizes mitochondrial integrity, and increases survival, making ANT1 a component in ROS management and heart protection during ischemia.

Key messages

  • ANT1 overexpression reduces infarct size and increases survival after infarction.

  • ANT1 overexpression compensates restricted ANT expression and function in infarcted hearts.

  • Increased ANT1 expression enhances mitochondrial integrity.

  • ANT1-overexpressing hearts reduce oxidative stress by decreasing ROS generation.

  • ANT1 is a component in ROS management and heart protection.

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Acknowledgements

This work was supported by the “Deutsche Forschungsgemeinschaft (DFG)” through the Sonderforschungsbereich Transregio 19, projects C7, C3, Z3.

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    Authors and Affiliations

    1. Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany

      Inga Klumpe, Ursula Rauch, Ulf Landmesser, Heinz-Peter Schultheiss & Andrea Dörner

    2. Institute of Biochemistry, Freie Universität Berlin, Berlin, Germany

      Inga Klumpe

    3. Berlin-Brandenburg Centre for Regenerative Therapies, Charité, Universitätsmedizin Berlin, Berlin, Germany

      Konstantinos Savvatis & Carsten Tschöpe

    4. Department of Cardiology, Barts Heart Centre, London, UK

      Konstantinos Savvatis

    5. Department of General and Interventional Cardiology, University Heart Centre, Hamburg, Germany

      Dirk Westermann

    6. Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

      Carsten Tschöpe

    7. Department of Cardiology, Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

      Andrea Dörner

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    1. Inga Klumpe
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    Correspondence to Andrea Dörner.

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    Inga Klumpe and Konstantinos Savvatis contributed equally to this work.

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    Klumpe, I., Savvatis, K., Westermann, D. et al. Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress. J Mol Med 94, 645–653 (2016). https://doi.org/10.1007/s00109-016-1413-4

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    • DOI: https://doi.org/10.1007/s00109-016-1413-4

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