title: Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse.
abstract: Essentials Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. Valproic acid increased tissue plasminogen activator expression in vascular endothelium. Valproic acid reduced fibrin deposition and thrombus formation after vascular injury.
  
  
  
  Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Larsson
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.|Heart Research Institute, Charles Perkins Centre, The University of Sydney, Sydney, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Alwis
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.|Molecular Neurotrauma and Haemostasis, Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Niego
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.|Molecular Neurotrauma and Haemostasis, Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Sashindranath
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Fogelstrand
authors.affiliation: Heart Research Institute, Charles Perkins Centre, The University of Sydney, Sydney, Australia.
authors.forename: M C L
authors.initials: MC
authors.lastname: Wu
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Glise
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Magnusson
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.|Molecular Neurotrauma and Haemostasis, Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Daglas
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Bergh
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.|Heart Research Institute, Charles Perkins Centre, The University of Sydney, Sydney, Australia.
authors.forename: S P
authors.initials: SP
authors.lastname: Jackson
authors.affiliation: Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.|Molecular Neurotrauma and Haemostasis, Central Clinical School, Monash University, Melbourne, Australia.
authors.forename: R L
authors.initials: RL
authors.lastname: Medcalf
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Jern
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005342:Fibrinolysis; D006470:Hemorrhage; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010979:Platelet Function Tests; D012333:RNA, Messenger / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014635:Valproic Acid; D010959:Tissue Plasminogen Activator
keywords: HDAC inhibitor; fibrinolysis; thrombosis; tissue-type plasminogen activator; valproic acid