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Am J Physiol Heart Circ Physiol 292: H333-H341, 2007. First published September 1, 2006; doi:10.1152/ajpheart.00078.2006
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Short-cycle hypoxia in the intact heart: hypoxia-inducible factor 1 signaling and the relationship to injury threshold

Divisions of ¹Cardiology and ²Genomics and Development, Department of Pediatrics, University of Washington, and ³Children's Hospital and Regional Medical Center, Seattle, Washington; and ⁴Qinghai-Tibet High Altitude Physiology Collaborative Group, Key Laboratory of Hypoxia Physiology, Chinese Academy of Sciences, Shanghai, China

Submitted 18 January 2006 ; accepted in final form 23 August 2006

Hypoxia-inducible factor 1 (HIF-1) transcriptionally activates multiple genes, which regulate metabolic cardioprotective and cross-adaptive mechanisms. Hypoxia and several other stimuli induce the HIF-1 signaling cascade, although little data exist regarding the stress threshold for activation in heart. We tested the hypothesis that relatively mild short-cycle hypoxia, which produces minimal cardiac dysfunction and no sustained or major disruption in energy state, can induce HIF-1 activation. We developed a short-cycle hypoxia protocol in isolated perfused rabbit heart to test this hypothesis. By altering cycling conditions, we identified a specific cycle with O₂ content and duration that operated near a threshold for causing functional injury in these rabbit hearts. Mild short-cycle hypoxia for 46 min elevated HIF-1 mRNA and protein within 45 min after reoxygenation. Expression also increased for multiple HIF-1 target genes, such as VEGF and heme oxygenase 1. After mild hypoxia, VEGF protein accumulation occurred, although HIF-1 and VEGF protein accumulation were suppressed after more severe hypoxia, which also caused depletion of ATP and nondiffusible nucleotides. In summary, these results indicate that mild near-threshold hypoxia induces HIF-1 cascade, but more severe hypoxia suppresses protein accumulation for this transcription factor and the target genes. Posttranscriptional suppression of these proteins occurs under conditions of altered energy state, exemplified by ATP depletion.

ATP; heme oxygenase; oxygen consumption; reoxygenation; vascular endothelial growth factor

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