Hypoxia causes downregulation of protein and RNA synthesis in noncontracting Mammalian cardiomyocytes.
The aim was to identify energy-consuming processes, other than contraction, downregulated during moderate hypoxia ( approximately 5 micromol/L, 0.5% O(2)) and severe hypoxia (<0.5 micromol/L, <0.05% O(2)) in isolated neonatal cardiomyocytes. The metabolic response of cardiomyocytes to moderate and severe hypoxia was assessed by measuring rates of energy consumption and energetic status of cells maintained under these conditions. We found that the rates of energy production were decreased during both forms of hypoxia. Decreased rates of energy production under moderate hypoxia were associated with reduced energy wastage through a downregulation of proton leak in the mitochondria. Cellular protein synthesis and RNA synthesis, major energy-consuming pathways, were downregulated only during severe hypoxia, when oxygen concentrations were low enough to induce energetic stress (quantitatively defined as being any situation in which phosphocreatine concentrations had fallen by > or = 40%). Our results suggest that energetic stress is the signal responsible for this downregulation.
Casey
Tammy M
TM
Department of Biochemistry, The University of Western Australia, Crawley, Australia. tmcasey@cyllene.uwa.edu.au
Pakay
Julian L
JL
Guppy
Michael
M
Arthur
Peter G
PG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000935:Antifungal Agents / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology*; D002469:Cell Separation; D015536:Down-Regulation / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008689:Methacrylates; D008928:Mitochondria / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000502:physiology; D010725:Phosphocreatine / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
D000935:Antifungal Agents; D015852:Eukaryotic Initiation Factor-2; D008689:Methacrylates; D011506:Proteins; D013844:Thiazoles; D010725:Phosphocreatine; D012313:RNA; C030517:myxothiazol; D000255:Adenosine Triphosphate; D012964:Sodium; D011188:Potassium; D010100:Oxygen