title: Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress.
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.
  
  
  
  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.
authors.affiliation: Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.|Institute of Biochemistry, Freie Universität Berlin, Berlin, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Klumpe
authors.affiliation: Berlin-Brandenburg Centre for Regenerative Therapies, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Department of Cardiology, Barts Heart Centre, London, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Savvatis
authors.affiliation: Department of General and Interventional Cardiology, University Heart Centre, Hamburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.affiliation: Berlin-Brandenburg Centre for Regenerative Therapies, Charité, Universitätsmedizin Berlin, Berlin, Germany.|Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.affiliation: Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Rauch
authors.affiliation: Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Landmesser
authors.affiliation: Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.affiliation: Department of Cardiology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. andrea.doerner@charite.de.|Department of Cardiology, Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. andrea.doerner@charite.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dörner
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics* / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D008929:Mitochondria, Heart / Q000187:drug effects / Q000235:genetics*; D009203:Myocardial Infarction / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D061251:Primary Cell Culture; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D033741:Adenine Nucleotide Translocator 1; D000447:Aldehydes; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D002374:Catalase; C505410:Casp3 protein, rat; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal
keywords: Adenine nucleotide translocase; Cardioprotection; Hypoxia; Ischemia; Mitochondria; Reactive oxygen species