Histone deacetylase inhibitors stimulate tissue-type plasminogen activator production in vascular endothelial cells

Pia Larsson, Niklas Bergh, Emma Lu, Erik Ulfhammer, Mia Magnusson, Karin Wåhlander, Lena Karlsson, Sverker Jern

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)

Abstract

A reduced capacity for acute tissue-type plasminogen activator (t-PA) release is likely to be associated with an impaired endogenous defense against intravascular thrombosis. Efficient approaches to pharmacologically restore a defective t-PA release have been lacking, but recent observations suggest that histone deacetylase inhibitors (HDACis) enhance t-PA production in vitro. HDACis have diverse chemical structures and different HDAC-enzyme sub-class targeting. We here compared the effects of several clinically used HDACis on t-PA production in endothelial cells. Human umbilical vein endothelial cells were exposed to a panel of 11 different HDACis and t-PA mRNA and protein levels were quantified. All HDACis dose-dependently stimulated t-PA mRNA and protein expression with similar maximal efficacy but with different potencies. Already at low concentrations, the majority of inhibitors caused significant and sustained effects on t-PA production. In addition, selected HDACis were capable of normalizing t-PA production when suppressed by the inflammatory cytokine TNF-α. We conclude that HDACis targeting classical HDAC enzymes are powerful inducers of t-PA expression in cultured endothelial cells and could be promising candidates for pharmacological modulation of endogenous fibrinolysis in man.

Original languageEnglish
Pages (from-to)185-192
Number of pages8
JournalJournal of Thrombosis and Thrombolysis
Volume35
Issue number2
DOIs
Publication statusPublished - 1 Feb 2013
Externally publishedYes

Keywords

  • Endothelial cell
  • Fibrinolysis
  • HDAC inhibitor
  • Tissue-type plasminogen activator

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