title: Histone deacetylase inhibition enhances tissue plasminogen activator release capacity in atherosclerotic man.
abstract: The expression of the tissue plasminogen activator (t-PA) gene appears to be under epigenetic control and can be affected by histone deacetylation inhibition. The study aimed to test if histone deacetalyase inhibitor treatment lead to increased t-PA release or reduced exhaustion in t-PA release in response to stimulation, as well as change in plasminogen activator inhibitor-1 (PAI-1) in subjects with coronary disease. In this clinical study, 16 post-myocardial infarction subjects, the perfused forearm model was used with isoprenaline provocation during 20 minutes, to stimulate local t-PA release. Each subject was measured twice on the same day (repeated stimuli sequences) as well as on two different occasions, without treatment and after four weeks of treatment with valproic acid (500 mg, twice daily). Net forearm release for t-PA in response to isoprenaline at minutes 1.5, 3, 6, 9, 12, 15 and 18 was measured, allowing assessment of cumulative t-PA release. There was a reduction in the exhaustion of cumulative t-PA release during repeated and prolonged stimulation with valproic acid treatment compared to non-treatment. Plasma PAI-1 antigen was decreased following treatment compared to non-treatment (18.4 ± 10.0 vs. 11.0 ± 7.1 nanograms/ml respectively, mean with 95% confidence interval). These findings demonstrate that histone deacetylation inhibition increases the capacity for endogenous t-PA release in subjects with vascular disease. Furthermore, the fibrinolytic balance is favored with suppressed PAI-1 levels. More studies are needed to establish the clinical relevance of these findings.
  
  
  BACKGROUND
  EU Clinical Trials Register 2012-004950-27.
authors: Anesthesiology and Intensive Care Medicine, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Kristina
authors: K
authors: Svennerholm
authors: Anesthesiology and Intensive Care Medicine, Institute for Surgical and Perioperative Science, Umeå University, Umeå, Sweden.
authors: Michael
authors: M
authors: Haney
authors: Anesthesiology and Intensive Care Medicine, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Björn
authors: B
authors: Biber
authors: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Erik
authors: E
authors: Ulfhammer
authors: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Ott
authors: O
authors: Saluveer
authors: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Pia
authors: P
authors: Larsson
authors: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Elmir
authors: E
authors: Omerovic
authors: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Sverker
authors: S
authors: Jern
authors: The Wallenberg Laboratory for Cardiovascular Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Niklas
authors: N
authors: Bergh
mesh_terms: D000368:Aged; D005260:Female; D005542:Forearm / Q000098:blood supply; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood*; D011446:Prospective Studies; D010959:Tissue Plasminogen Activator / Q000097:blood*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D010959:Tissue Plasminogen Activator; D007545:Isoproterenol