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Ann Thorac Surg 2004;77:1751-1755
© 2004 The Society of Thoracic Surgeons

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Original article: general thoracic

Upregulated hypoxia-inducible factor-1 DNA binding activity to the vascular endothelial growth factor-A promoter mediates increased vascular permeability in donor lung grafts

^a Laboratory for Cardiovascular Research, Department of Anatomy, University of Vienna, Vienna, Austria
^b Department of Cardiothoracic Surgery, University of Vienna, Vienna, Austria

Accepted for publication October 10, 2003.

^* Address reprint requests to Dr Aharinejad, Laboratory for Cardiovascular Research, Department of Anatomy, University of Vienna, Waehringerstrasse 13, A-1090 Vienna, Austria
e-mail: ahas{at}univie.ac.at

BACKGROUND: Transplantation-induced hypoxia results in enhanced vascular permeability and tissue vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) overexpression in donor lung grafts. Promoter studies have uncovered a hypoxia-inducible factor (HIF)-1 binding site (HBS) in 5'-flanking region of VEGF gene that regulates the hypoxia-induced expression of VEGF; and ET-1 potently stimulates VEGF-A production. We hypothesized that HIF-1 regulates VEGF-mediated vascular permeability in lung grafts.

METHODS: We studied the mRNA and protein expression of HIF-1 and its protein-binding capacity to the HBS of the VEGF gene in biopsies of preserved donor and control lungs, using real-time reverse transcription-polymerase chain reaction, Western blotting, and electrophoretic mobility shift assay. Wet-to-dry lung weight ratio was measured in donor and control lungs.

RESULTS: While HIF-1 mRNA expression was unchanged, HIF-1ß was downregulated (p < 0.05) in donor versus control lungs. Protein expression of both, HIF-1 and -ß was significantly upregulated in donor lung grafts. HIF-1 binding to the HBS of the VEGF promoter as well as tissue fluid content were increased in donor lung biopsies versus controls (p < 0.05).

CONCLUSIONS: These data indicate that upregulated HIF-1 DNA binding activity to the HBS of VEGF-A most likely contributes to elevated VEGF levels in preserved lung grafts. Unchanged HIF-1 mRNA expression did not affect HIF-1 protein levels. Endothelin-1 increases HIF-1 accumulation and activates HIF-1 transcription complex in vitro. Therefore, ET-1-mediated increased HIF-1 protein stability most likely leads to transcriptional activation of VEGF during lung graft preservation. Targeting HIF might be of benefit to counteract edema formation in preserved lung grafts.

This article has been cited by other articles:

				Q. Zhang, O. W. Moe, J. A. Garcia, and C. C. W. Hsia Regulated expression of hypoxia-inducible factors during postnatal and postpneumonectomy lung growth Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L880 - L889. [Abstract] [Full Text] [PDF]