title: Accelerated mitochondrial adenosine diphosphate/adenosine triphosphate transport improves hypertension-induced heart disease.
abstract: BACKGROUND
  Strong evidence suggests that mitochondrial malfunction, which leads to disturbed energy metabolism and stimulated apoptosis, is a linchpin in the induction and manifestation of cardiac failure. An adequate exchange of ATP and ADP over the inner mitochondrial membrane by the adenine nucleotide translocase (ANT) is thereby essential to guarantee the cellular energy supply.
  
  
  RESULTS
  To explore the effect of an ameliorated mitochondrial ATP/ADP transportation on cardiac dysfunction, we generated transgenic rats overexpressing ANT1 in the heart (ANT rats) and crossed them with renin-overexpressing rats (REN rats) suffering from hypertension-induced cardiac insufficiency. Cardiac-specific ANT1 overexpression resulted in a higher ATP/ADP transportation and elevated activities of respiratory chain complexes. Increased ANT activity in double-transgenic (ANT/REN) animals did not influence excessive hypertension seen in REN rats. Hypertension-induced cardiac hypertrophy in the REN rats was prevented by parallel ANT1 overexpression, however, and left ventricular function remarkably improved. The ANT1 overexpression led to a reduction in fibrosis and an improvement in cardiac tissue architecture. Consequently, the survival rate of ANT/REN rats was enhanced. Further investigations into the cardioprotective mechanism of ANT1 overexpression revealed improved mitochondrial structure and function and significantly reduced apoptosis in ANT/REN rats, shown by lowered cytosolic/mitochondrial cytochrome c ratio, reduced caspase 3 level, and prevented DNA degradation.
  
  
  CONCLUSIONS
  Myocardial ANT1 overexpression protects against hypertension-induced cardiac pathology. Thus, the improvement in mitochondrial function may be a basic principle for new strategies in treating heart disease.
authors.affiliation: Charité-Universitätsmedizin, Campus Benjamin Franklin, Department of Cardiology and Pneumonology, Hindenburgdamm 30, 12200 Berlin, Germany. thomas.walther@charite.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Anja
authors.initials: A
authors.lastname: Sterner-Kock
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Silvia
authors.initials: S
authors.lastname: Heringer-Walther
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Alen
authors.initials: A
authors.lastname: Nikolic
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Linda
authors.initials: L
authors.lastname: Ebermann
authors.forename: Wolf-Eberhard
authors.initials: WE
authors.lastname: Siems
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Andrea
authors.initials: A
authors.lastname: Dörner
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001692:Biological Transport / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006331:Heart Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D008929:Mitochondria, Heart / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
chemical_list: D033741:Adenine Nucleotide Translocator 1; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; D053148:Caspase 3; D012083:Renin