title: Profibrinolytic effect of the epigenetic modifier valproic acid in man.
abstract: OBJECTIVE
  The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro.
  
  
  RESULTS
  The trial had a cross-over design where healthy men (n = 10), were treated with VPA (Ergenyl Retard) 500 mg depot tablets twice daily for 2 weeks. Capacity for stimulated t-PA release was assessed in the perfused-forearm model using intra-brachial Substance P infusion and venous occlusion plethysmography. Each subject was investigated twice, untreated and after VPA treatment, with 5 weeks wash-out in-between. VPA treatment resulted in considerably decreased levels of circulating PAI-1 antigen from 22.2 (4.6) to 10.8 (2.1) ng/ml (p<0.05). It slightly decreased the levels of circulating venous t-PA antigen (p<0.05), and the t-PA:PAI-1 antigen ratio increased (p<0.01). Substance P infusion resulted in an increase in forearm blood flow (FBF) on both occasions (p<0.0001 for both). The acute t-PA release in response to Substance P was not affected by VPA (p = ns).
  
  
  CONCLUSIONS
  Valproic acid treatment lowers plasma PAI-1 antigen levels and changes the fibrinolytic balance measured as t-PA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by VPA treatment observed in recent pharmacoepidemiological studies.
  
  
  BACKGROUND
  The EU Clinical Trials Register 2009-011723-31.
authors.affiliation: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ott
authors.initials: O
authors.lastname: Saluveer
authors.affiliation: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Larsson
authors.affiliation: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Ridderstråle
authors.affiliation: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Cardiology, Landspitali University Hospital and the University of Iceland, Reykjavik, Iceland.
authors.forename: Thórdís J
authors.initials: TJ
authors.lastname: Hrafnkelsdóttir
authors.affiliation: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sverker
authors.initials: S
authors.lastname: Jern
authors.affiliation: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Bergh
mesh_terms: D000368:Aged; D018592:Cross-Over Studies; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000235:genetics; D005342:Fibrinolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D014635:Valproic Acid; D010959:Tissue Plasminogen Activator