Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress
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Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress. / Klumpe, Inga; Savvatis, Konstantinos; Westermann, Dirk; Tschöpe, Carsten; Rauch, Ursula; Landmesser, Ulf; Schultheiss, Heinz-Peter; Dörner, Andrea.
in: J MOL MED, Jahrgang 94, Nr. 6, 06.2016, S. 645-653.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Transgenic overexpression of adenine nucleotide translocase 1 protects ischemic hearts against oxidative stress
AU - Klumpe, Inga
AU - Savvatis, Konstantinos
AU - Westermann, Dirk
AU - Tschöpe, Carsten
AU - Rauch, Ursula
AU - Landmesser, Ulf
AU - Schultheiss, Heinz-Peter
AU - Dörner, Andrea
PY - 2016/6
Y1 - 2016/6
N2 - UNLABELLED: 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.
AB - UNLABELLED: 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.
KW - Adenine Nucleotide Translocator 1/genetics
KW - Aldehydes/metabolism
KW - Animals
KW - Caspase 3/genetics
KW - Catalase/genetics
KW - Cell Hypoxia
KW - Cell Survival
KW - Cytochromes c/metabolism
KW - Gene Expression Regulation
KW - Hydrogen Peroxide/pharmacology
KW - Male
KW - Membrane Potential, Mitochondrial/drug effects
KW - Mitochondria, Heart/drug effects
KW - Myocardial Infarction/genetics
KW - Myocytes, Cardiac/drug effects
KW - Oxidative Stress
KW - Primary Cell Culture
KW - Protein Carbonylation/drug effects
KW - Rats
KW - Rats, Transgenic
KW - Reactive Oxygen Species/metabolism
KW - Signal Transduction
KW - Survival Analysis
U2 - 10.1007/s00109-016-1413-4
DO - 10.1007/s00109-016-1413-4
M3 - SCORING: Journal article
C2 - 27080394
VL - 94
SP - 645
EP - 653
JO - J MOL MED
JF - J MOL MED
SN - 0946-2716
IS - 6
ER -
