title: Histone deacetylase inhibitors stimulate tissue-type plasminogen activator production in vascular endothelial cells.
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.
authors.affiliation: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. pia.larsson@gu.se
authors.forename: Pia
authors.initials: P
authors.lastname: Larsson
authors.forename: Niklas
authors.initials: N
authors.lastname: Bergh
authors.forename: Emma
authors.initials: E
authors.lastname: Lu
authors.forename: Erik
authors.initials: E
authors.lastname: Ulfhammer
authors.forename: Mia
authors.initials: M
authors.lastname: Magnusson
authors.forename: Karin
authors.initials: K
authors.lastname: Wåhlander
authors.forename: Lena
authors.initials: L
authors.lastname: Karlsson
authors.forename: Sverker
authors.initials: S
authors.lastname: Jern
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; D010959:Tissue Plasminogen Activator