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Am J Physiol Heart Circ Physiol (September 1, 2006). doi:10.1152/ajpheart.00078.2006
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Submitted on January 18, 2006
Accepted on August 23, 2006

Short Cycle Hypoxia in the Intact Heart: Hypoxia Inducible Factor 1-{alpha} Signaling and the Relationship to Injury Threshold

Xue-Han Ning1, Shi-Han Chen2, Norman E. Buroker3, Chen-Su Xu4, Fu-Ren Li4, Shu-Peng Li4, De-song Song4, Ming Ge3, Outi M. Hyyti5, Min Zhang6, and Michael A. Portman1*

1 Cardiology, Children's Hospital and Regional Medical Center, Seattle, Washington, United States; Pediatrics, University of Washington, Seattle, Washington, United States
2 Genome Sciences, Children's Hospital and Regional Medical Center, Seattle, Washington, United States; Pediatrics, University of Washington, Seattle, Washington, United States
3 Cardiology, Children's Hospital and Regional Medical Center, Seattle, Washington, United States
4 Key Laboratory of Hypoxia Physiology, Chinese Academy of Sciences, Shanghai, China
5 Pediatrics, University of Washington, Seattle, Washington, United States; Cardiology, Children's Hospital and Regional Medical Center, Seattle, Washington, United States
6 Genome Sciences, Children's Hospital and Regional Medical Center, Seattle, Washington, United States

* To whom correspondence should be addressed. E-mail: michael.portman{at}seattlechildrens.org.

Hypoxia inducible factor1{alpha} (HIF-1{alpha}) transcriptionally activates multiple genes, which regulate metabolic cardioprotective and cross-adaptive mechanisms. Hypoxia and several other stimuli induce the HIF-1{alpha} signaling cascade, though 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, which operated near a threshold for causing functional injury in these rabbit hearts. Mild short-cycle hypoxia for 46 minutes elevated HIF-1{alpha} mRNA and protein within 45 minutes after reoxygenation. Expression also increased for multiple HIF-1{alpha} target genes, such as vascular endothelial growth factor (VEGF) and heme oxygenase 1(Hmox1). After mild hypoxia, VEGF protein accumulation occurred, although HIF-1{alpha} and VEGF protein accumulation were suppressed after more severe hypoxia, which also caused depletion of ATP and non-diffusible nucleotides. In summary, these results indicate that mild near-threshold hypoxia induces HIF-1{alpha} 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.




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 Am. J. Physiol. Heart Circ. Physiol.Home page
X.-H. Ning, E. Y. Chi, N. E. Buroker, S.-H. Chen, C.-S. Xu, Y.-T. Tien, O. M. Hyyti, M. Ge, and M. A. Portman
Moderate hypothermia (30{degrees}C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion
Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2119 - H2128.
[Abstract] [Full Text] [PDF]


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