title: Role of histone acetylation in the stimulatory effect of valproic acid on vascular endothelial tissue-type plasminogen activator expression.
abstract: OBJECTIVE
  Stimulated release of tissue-type plasminogen activator (t-PA) is pivotal for an intravascular fibrinolytic response and protects the circulation from occluding thrombosis. Hence, an impaired t-PA production is associated with increased risk for atherothrombotic events. A pharmacological means to stimulate the production of this enzyme may thus be desirable. We investigated if the anti-epileptic drug valproic acid (VPA) is capable of enhancing t-PA expression in vitro in vascular endothelial cells, and further examined if its histone deacetylase (HDAC)-inhibitory activity is of importance for regulating t-PA expression.
  
  
  RESULTS
  Human endothelial cells were exposed to valproic acid and t-PA mRNA and protein levels were quantified. Potential changes in histone acetylation status globally and at the t-PA promoter were examined by western blot and chromatin immunoprecipitation. Valproic acid dose-dependently stimulated t-PA mRNA and protein expression in endothelial cells reaching a 2-4-fold increase at clinically relevant concentrations and 10-fold increase at maximal concentrations. Transcription profiling analysis revealed that t-PA is selectively targeted by this agent. Augmented histone acetylation was detected at the t-PA transcription start site, and an attenuated VPA-response was observed with siRNA knock of HDAC3, HDAC5 and HDAC7.
  
  
  CONCLUSIONS
  Valproic acid induces t-PA expression in cultured endothelial cells, and this is associated with increased histone acetylation at the t-PA promoter. Given the apparent potency of valproic acid in stimulating t-PA expression in vitro this substance may be a candidate 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.
authors.forename: Pia
authors.initials: P
authors.lastname: Larsson
authors.forename: Erik
authors.initials: E
authors.lastname: Ulfhammer
authors.forename: Mia
authors.initials: M
authors.lastname: Magnusson
authors.forename: Niklas
authors.initials: N
authors.lastname: Bergh
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lunke
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Robert L
authors.initials: RL
authors.lastname: Medcalf
authors.forename: Per-Arne
authors.initials: PA
authors.lastname: Svensson
authors.forename: Lena
authors.initials: L
authors.lastname: Karlsson
authors.forename: Sverker
authors.initials: S
authors.lastname: Jern
mesh_terms: D000107:Acetylation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003331:Coronary Vessels / Q000166:cytology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology*; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006487:Hemostasis / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014635:Valproic Acid; D010959:Tissue Plasminogen Activator; D006655:Histone Deacetylases