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(Circulation Research. 2002;90:777.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Hypoxia Causes Downregulation of Protein and RNA Synthesis in Noncontracting Mammalian Cardiomyocytes

Tammy M. Casey, Julian L. Pakay, Michael Guppy, Peter G. Arthur

From the Department of Biochemistry (T.M.C., J.L.P., M.G., P.G.A.), The University of Western Australia, Crawley, Australia, and the Western Australian Institute for Medical Research (T.M.C., P.G.A.), Perth, Australia.

Correspondence to Tammy Casey, Department of Biochemistry, The University of Western Australia, 35 Stirling Hwy, Crawley, WA, 6009, Australia. E-mail tmcasey{at}cyllene.uwa.edu.au

The aim was to identify energy-consuming processes, other than contraction, downregulated during moderate hypoxia (5 µmol/L, 0.5% O₂) and severe hypoxia (<0.5 µmol/L, <0.05% O₂) 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 40%). Our results suggest that energetic stress is the signal responsible for this downregulation.

Key Words: cardiomyocytes • protein synthesis • RNA synthesis • Na⁺,K⁺-ATPase activity • proton leak

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