title: Transient upregulation of PGC-1alpha diminishes cardiac ischemia tolerance via upregulation of ANT1.
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.
authors.affiliation: Translational Medicine Branch, NHLBI, NIH, Bethesda, MD 20892-1454, USA.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lynn
authors.forename: Mark V
authors.initials: MV
authors.lastname: Stevens
authors.forename: Renee P
authors.initials: RP
authors.lastname: Wong
authors.forename: Darin
authors.initials: D
authors.lastname: Carabenciov
authors.forename: Jeremy
authors.initials: J
authors.lastname: Jacobson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005434:Flow Cytometry; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D033741:Adenine Nucleotide Translocator 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors