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Cardiovascular Research Advance Access first published online on September 17, 2009
This version [Corrected Proof] published online on October 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp314
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Krüppel-like factor 15 regulates BMPER in endothelial cells

Thomas Helbing1, Franziska Volkmar1, Ulrich Goebel2, Jennifer Heinke1, Philipp Diehl1, Heike L. Pahl2, Christoph Bode1, Cam Patterson3 and Martin Moser1,*

1 Department of Cardiology, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
2 Department of Anesthesiology and Critical Care Medicine, University of Freiburg, Freiburg, Germany
3 Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

* Corresponding author. Tel: +49 7612703546, Fax: +49 7612703254, Email: martin.moser{at}uniklinik-freiburg.de

Aims: Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. Previous studies have shown that BMP endothelial cell precursor-derived regulator (BMPER) plays an important role in endothelial cell function and blood vessel formation. BMPER is a key regulator of BMP4 activity and a prerequisite for BMP pathway activation by BMP4 in endothelial cells. Here, we characterize the BMPER promoter and elucidate mechanisms of BMPER regulation.

Methods and results: To investigate transcriptional mechanisms of BMPER expression, the murine BMPER promoter was cloned and characterized. A series of 5' deletions of the BMPER promoter revealed that the proximal promoter contains activating cis-elements. By overexpression or siRNA-based knockdown, we demonstrate that BMPER expression is activated by Krüppel-like factor (KLF) 15. As determined by gelshift analyses, KLF15 binds directly to a predicted KLF-binding element at –284 bp within the BMPER promoter. Co-expression experiments show that Sp1 acts as an antagonist for KLF15-induced promoter activation. Endothelin-1 was identified as a potent inhibitor of KLF15 and BMPER expression in endothelial cells, suggesting that KLF15 is a transducer of endothelin-1 activity on BMPER expression. The selective ETB endothelin receptor antagonist BQ788 abolished the downregulation of BMPER expression by endothelin-1.

Conclusion: Mechanistically, we found that KLF15 is a strong and direct activator of the BMPER expression. BMPER is downregulated by endothelin-1 in a dose-dependent fashion and in parallel to KLF15. As KLF15 deficiency is accompanied by a vascular phenotype and BMPER is necessary for proper blood vessel formation, we suggest a chain of events in which the effects of endothelin-1 on BMPER are mediated by KLF15.

KEYWORDS BMPER; Bone morphogenetic protein; Regulation; Krüppel-like factor 15; Endothelial cell

Time for primary review: 22 days


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