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Transient upregulation of PGC-1alpha diminishes cardiac ischemia tolerance via upregulation of ANT1.
- Source :
-
Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2010 Oct; Vol. 49 (4), pp. 693-8. Date of Electronic Publication: 2010 Jul 01. - Publication Year :
- 2010
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Abstract
- Prolonged cardiac overexpression of the mitochondrial biogenesis regulatory transcriptional coactivator PGC-1alpha disrupts cardiac contractile function and its genetic ablation limits cardiac capacity to enhance workload. In contrast, transient induction of PGC-1alpha alleviates neuronal cell oxidative stress and enhances skeletal myotube anti-oxidant defenses. We explored whether transient upregulation of PGC-1alpha in the heart protects against ischemia-reperfusion injury. The transient induction of PGC-1alpha in the cardiac-restricted inducible PGC-1alpha transgenic mouse, increased PGC-1alpha protein levels 5-fold. Following 25 min of ischemia and 2h of reperfusion on a Langendorff perfusion apparatus, contractile recovery and the rate pressure product was significantly blunted in mice overexpressing PGC-1alpha vs. controls. Affymetrix gene array analysis showed a 3-fold PGC-1alpha-mediated upregulation of adenine nucleotide translocase 1 (ANT1). As ANT1 upregulation induces cardiomyocyte cell death we investigated whether the induction of ANT1 by PGC-1alpha contributes to this enhanced ischemia-stress susceptibility. Infection with adenovirus harboring PGC-1alpha into cardiac-derived H9c2 cells significantly upregulates ANT1 without changing basal cell viability. In response to anoxia-reoxygenation injury cell death is significantly increased following PGC-1alpha overexpression. This detrimental effect is abolished following siRNA knockdown of ANT1. Similarly, the attenuation of ANT-1 in the presence of PGC-1alpha overexpression preserves the mitochondrial membrane potential in response to hydrogen-peroxide stress. Interestingly, the isolated knockdown of ANT1 also protects H9c2 cells from anoxia-reoxygenation injury. Taken together these data suggest that transient induction of PGC-1alpha in the murine heart decreases ischemia-reperfusion contractile recovery and diminishes anoxia-reoxygenation tolerance in H9c2 cells. These adverse phenotypes appear to be mediated, in part, by PGC-1alpha induced upregulation of ANT1.<br /> (Published by Elsevier Ltd.)
- Subjects :
- Adenine Nucleotide Translocator 1 genetics
Animals
Cell Survival physiology
Cells, Cultured
Flow Cytometry
Membrane Potential, Mitochondrial physiology
Mice
Mice, Transgenic
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Rats
Reperfusion Injury genetics
Trans-Activators genetics
Transcription Factors
Adenine Nucleotide Translocator 1 metabolism
Reperfusion Injury metabolism
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-8584
- Volume :
- 49
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of molecular and cellular cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 20600099
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2010.06.008