Hypoxia, via stabilization of hypoxia-inducible factor HIF-1{alpha} is a direct and sufficient stimulus for brain-type natriuretic peptide induction

Alexander Weidemann (1) , Bernd Klanke , Michael Wagner , Tilmann Volk , Carsten Willam , Michael S. Wiesener , Kai Uwe Eckardt , Christina Warnecke

1 Medical Clinic 4, Nephrology and Hypertension

Brain-type Natriuretic Peptide (BNP) is a cardiac hormone with systemic hemodynamic 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 direct effects of hypoxia on BNP expression and the role of the hypoxia-inducible transcription factor (HIF) in BNP regulation. Using RNase protection assay we found a strong hypoxic induction of BNP mRNA expression in different cell lines and in cultured adult rat cardiomyoctes. Systemic hypoxia and exposure to 0.1% carbon monoxide induced BNP expression in the rodent myocardium in vivo, yet at a low amplitude. BNP promoter-driven luciferase expression increased 10-fold after hypoxic stimulation in transient transfections. Inactivation of four putative hypoxia-response elements (HRE) 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 and chromatin immunoprecipitation. SiRNA 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 therapeutical benefits of pharmacological HIF inducers.

Mots clés: Life Sciences

Alexander Weidemann, Bernd Klanke, Michael Wagner, Tilmann Volk, Carsten Willam, et al.. Hypoxia, via stabilization of hypoxia-inducible factor HIF-1{alpha} is a direct and sufficient stimulus for brain-type natriuretic peptide induction. Biochemical Journal, 2007, 409 (1), pp.233-242. ⟨10.1042/BJ20070629⟩. ⟨hal-00478800⟩