BNP (brain-type natriuretic peptide) is a cardiac hormone with systemic haemodynamic effects as well as local cytoprotective and antiproliferative properties. It is induced under a variety of pathophysiological conditions, including decompensated heart failure and myocardial infarction. Since regional hypoxia is a potential common denominator of increased wall stretch and myocardial hypoperfusion, we investigated the direct effects of hypoxia on BNP expression, and the role of the HIF (hypoxia-inducible transcription factor) in BNP regulation. Using an RNase protection assay we found a strong hypoxic induction of BNP mRNA expression in different cell lines and in cultured adult rat cardiomyocytes. Systemic hypoxia and exposure to 0.1% CO induced BNP expression in the rodent myocardium in vivo, although this was at a lower amplitude. BNP promoter-driven luciferase expression increased 10-fold after hypoxic stimulation in transient transfections. Inactivation of four putative HREs (hypoxia-response elements) in the promoter by site-directed mutagenesis revealed that the HRE at −466 nt was responsible for hypoxic promoter activation. A functional CACAG motif was identified upstream of this HRE. The HIF-1 complex bound specifically and inducibly only to the HRE at −466 nt, as shown by EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). siRNA (small interfering RNA)-mediated knockdown of HIF-1α, but not HIF-2α, interfered with hypoxic BNP mRNA induction and BNP promoter activation, confirming that BNP is a specific HIF-1α target gene. In conclusion, BNP appears to be part of the protective program steered by HIF-1 in response to oxygen deprivation. Induction of BNP may therefore contribute to the potential benefits of pharmacological HIF inducers in the treatment of ischaemic heart disease and heart failure.
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Research Article|
December 11 2007
Hypoxia, via stabilization of the hypoxia-inducible factor HIF-1α, is a direct and sufficient stimulus for brain-type natriuretic peptide induction
Alexander Weidemann;
Alexander Weidemann
1
*Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054 Erlangen, Germany
†Interdisciplinary Centre for Clinical Research (IZKF), University of Erlangen-Nuremberg, Maximiliansplatz 2, 91054 Erlangen
1To whom correspondence should be addressed at the present address: Department of Biology, Molecular Biology Section, University of California, San Diego, La Jolla, CA 92093-0377, U.S.A. (email aweidemann@ucsd.edu).
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Bernd Klanke;
Bernd Klanke
*Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054 Erlangen, Germany
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Michael Wagner;
Michael Wagner
‡Institute of Cellular and Molecular Physiology, University of Erlangen-Nuremberg, Waldstr. 6, 91054 Erlangen, Germany
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Tilmann Volk;
Tilmann Volk
‡Institute of Cellular and Molecular Physiology, University of Erlangen-Nuremberg, Waldstr. 6, 91054 Erlangen, Germany
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Carsten Willam;
Carsten Willam
*Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054 Erlangen, Germany
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Michael S. Wiesener;
Michael S. Wiesener
*Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054 Erlangen, Germany
†Interdisciplinary Centre for Clinical Research (IZKF), University of Erlangen-Nuremberg, Maximiliansplatz 2, 91054 Erlangen
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Kai-Uwe Eckardt;
Kai-Uwe Eckardt
*Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054 Erlangen, Germany
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Christina Warnecke
Christina Warnecke
*Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Krankenhausstr. 12, 91054 Erlangen, Germany
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Publisher: Portland Press Ltd
Received:
May 10 2007
Revision Received:
August 30 2007
Accepted:
September 07 2007
Accepted Manuscript online:
September 07 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 409 (1): 233–242.
Article history
Received:
May 10 2007
Revision Received:
August 30 2007
Accepted:
September 07 2007
Accepted Manuscript online:
September 07 2007
Citation
Alexander Weidemann, Bernd Klanke, Michael Wagner, Tilmann Volk, Carsten Willam, Michael S. Wiesener, Kai-Uwe Eckardt, Christina Warnecke; Hypoxia, via stabilization of the hypoxia-inducible factor HIF-1α, is a direct and sufficient stimulus for brain-type natriuretic peptide induction. Biochem J 1 January 2008; 409 (1): 233–242. doi: https://doi.org/10.1042/BJ20070629
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