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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/H550    most recent 00250.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Casals, G. Articles by Jiménez, W. PubMed PubMed Citation Articles by Casals, G. Articles by Jiménez, W.

Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes

¹Service of Biochemistry and Molecular Genetics, ²Department of Physiology I, ³Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, and ⁴Department of Cardiology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; and ⁵Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York

Submitted 12 March 2009 ; accepted in final form 16 June 2009

B-type natriuretic peptide (BNP) is a peptide hormone of myocardial origin with significant cardioprotective properties. Patients with myocardial ischemia present with high levels of BNP in plasma and elevated expression in the myocardium. However, the molecular mechanisms of BNP induction in the ischemic myocardium are not well understood. The aim of the investigation was to assess whether myocardial hypoxia induces the production of BNP in human ventricular myocytes. To test the hypothesis that reduced oxygen tension can directly stimulate BNP gene expression and release in the absence of hemodynamic or neurohormonal stimuli, we used an in vitro model system of cultured human ventricular myocytes (AC16 cells). Cells were cultured under normoxic (21% O₂) or hypoxic (5% O₂) conditions for up to 48 h. The accumulation of BNP, atrial natriuretic peptide (ANP), and vascular endothelial growth factor (VEGF) was then measured. Hypoxia stimulated the protein release of BNP and VEGF but not ANP. In concordance, the increased mRNA levels of BNP and VEGF but not ANP were found on culturing AC16 cells under hypoxic conditions. The analysis of the transcriptional activity of the hypoxia-inducible factor 1 (HIF-1) in nuclear extracts showed that HIF-1 activity was induced under hypoxic conditions. Finally, the treatment of AC16 cells with the HIF-1 inhibitor rotenone in hypoxia inhibited BNP and VEGF release. In conclusion, these data indicate that hypoxia induces the synthesis and secretion of BNP in human ventricular myocytes, likely through HIF-1-enhanced transcriptional activity.

B-type natriuretic peptides; hypoxia-inducible factor 1; myocardial ischemia; heart failure; vascular endothelial growth factor