Activation of the prolyl hydroxylase oxygen-sensor results in induction of GLUT1, heme oxygenase-1, and nitric-oxide synthase proteins and confers protection from metabolic inhibition to cardiomyocytes

Gary Wright, Joshua J. Higgin, Ronald T. Raines, Charles Jr Steenbergen, Elizabeth Murphy

Research output: Contribution to journalArticle

Abstract

Recently an oxygen-sensing/transducing mechanism has been identified as a family of O2-dependent prolyl hydroxylase domain-containing enzymes (PHD). In normoxia, PHD hydroxylates a specific proline residue that directs the degradation of constitutively synthesized hypoxia-inducible factor-1α. During hypoxia, the cessation of hydroxylation of this proline results in less degradation and thus increases hypoxia-inducible factor-1α protein levels. In this study we have examined the consequences of activating the PHD oxygen-sensing pathway in cultured neonatal myocytes using ethyl-3,4 dihydroxybenzoate and dimethyloxalylglycine, inhibitors that, similar to hypoxia, inhibit this family of O2-dependent PHD enzymes. Increased glucose uptake and enhanced glycolytic metabolism are classical cellular responses to hypoxia. Ethyl-3,4 dihydroxybenzoate treatment of cardiomyocyte cultures for 24 h increased [3H]deoxy-4-glucose uptake concurrent with an induction of GLUT1 protein. In addition, ethyl-3,4 dihydroxybenzoate, dimethyloxalylglycine, and hypoxia treatments were found to induce protein levels of nitricoxide synthase-2 and heme oxygenase-1, two important cardioregulatory proteins whose expression in response to hypoxic conditions is poorly understood. In conjunction with these changes in gene expression, activation of the PHD oxygen-sensing mechanism was found to preserve myocyte viability in the face of metabolic inhibition with cyanide and 2-deoxyglucose. These results point to a key role for the PHD pathway in the phenotypic changes that are observed in a hypoxic myocyte and may suggest a strategy to pharmacologically induce protection in heart.

Original languageEnglish (US)
Pages (from-to)20235-20239
Number of pages5
JournalJournal of Biological Chemistry
Volume278
Issue number22
DOIs
StatePublished - May 30 2003
Externally publishedYes

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Prolyl Hydroxylases
Oxygen sensors
Heme Oxygenase-1
Cardiac Myocytes
Nitric Oxide Synthase
Chemical activation
Oxygen
Enzymes
Proteins
Muscle Cells
Hypoxia-Inducible Factor 1
Proline
Glucose Transporter Type 1
Glucose
Degradation
Hydroxylation
Deoxyglucose
Cyanides
Metabolism
Gene expression

ASJC Scopus subject areas

  • Biochemistry

Cite this

Activation of the prolyl hydroxylase oxygen-sensor results in induction of GLUT1, heme oxygenase-1, and nitric-oxide synthase proteins and confers protection from metabolic inhibition to cardiomyocytes. / Wright, Gary; Higgin, Joshua J.; Raines, Ronald T.; Steenbergen, Charles Jr; Murphy, Elizabeth.

In: Journal of Biological Chemistry, Vol. 278, No. 22, 30.05.2003, p. 20235-20239.

Research output: Contribution to journalArticle

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