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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5669-5679. Prepublished online as a Blood First Edition Paper on April 7, 2009; DOI 10.1182/blood-2009-01-196485. This Article Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2009-01-196485v1 113/22/5669    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Urbich, C. Articles by Dimmeler, S. Search for Related Content PubMed PubMed Citation Articles by Urbich, C. Articles by Dimmeler, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 13, 2009 Accepted February 11, 2009 HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells Carmen Urbich, Lothar Rossig, David Kaluza, Michael Potente, Jes-Niels Boeckel, Andrea Knau, Florian Diehl, Jian-Guo Geng, Wolf-Karsten Hofmann, Andreas M. Zeiher, and Stefanie Dimmeler* Molecular Cardiology, Department of Medicine III, University of Frankfurt, Frankfurt, Germany Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, United States Department of Hematology, Oncology and Transfusion Medicine, Charite, University Hospital Benjamin Franklin, Berlin, Germany * Corresponding author; email: dimmeler{at}em.uni-frankfurt.de. Class IIa histone deacetylases (HDACs) are signal-responsive regulators of gene expression involved in vascular homeostasis. To investigate the differential role of class IIa HDACs for the regulation of angiogenesis, we used siRNA to specifically suppress the individual HDAC isoenzymes. Among the HDAC isoforms tested, silencing of HDAC5 exhibited a unique pro-angiogenic effect evidenced by increased endothelial cell migration, sprouting and tube formation. Consistently, overexpression of HDAC5 decreased sprout formation, indicating that HDAC5 is a negative regulator of angiogenesis. The anti-angiogenic activity of HDAC5 was independent of MEF2 binding and its deacetylase activity, but required a nuclear localization indicating that HDAC5 might affect the transcriptional regulation of gene expression. To identify putative HDAC5 targets, we performed microarray expression analysis. Silencing of HDAC5 increased the expression of fibroblast growth factor 2 (FGF2) and angiogenic guidance factors including Slit2. Antagonization of FGF2 or Slit2 reduced sprout induction in response to HDAC5 siRNA. ChIP assays demonstrate that HDAC5 binds to the promoter of FGF2 and Slit2. In summary, HDAC5 represses angiogenic genes, like FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. The de-repression of angiogenic genes by HDAC5 inactivation may provide a useful therapeutic target for induction of angiogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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