Profibrinolytic effect of the epigenetic modifier valproic acid in man.

Ott Saluveer,Pia Larsson,Sverker Jern,Wilhelm Ridderstråle,Thórdís J Hrafnkelsdóttir,Niklas Bergh

doi:10.1371/journal.pone.0107582

Abstract

AimsThe 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.Methods and ResultsThe 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).ConclusionValproic 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.Trial RegistrationThe EU Clinical Trials Register 2009-011723-31

Highlights

Cardiovascular disease is a major cause of death and disability globally
Valproic acid treatment lowers plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels and changes the fibrinolytic balance measured as tPA/PAI-1 ratio in a profibrinolytic direction. This may in part explain the reduction in incidence of myocardial infarctions by valproic acid (VPA) treatment observed in recent pharmacoepidemiological studies
11 potential subjects were enrolled in the study after responding to the advertisement in the local newspaper. 10 subjects were included in the trial

Summary

Introduction

Current preventive antithrombotic treatment options target the coagulation cascade or the platelets. The drugs must be dosed at a suboptimal clot-preventing level that leaves the patient with a substantial residual risk, because of the dosedepending risk of severe bleeding complications. In vivo the endogenous fibrinolytic system has an important role in preventing excessive clot formation. The balance between the key activator of fibrinolysis, tissue plasminogen activator (t-PA), and its main inhibitor plasminogen activator inhibitor-1 (PAI-1) is crucial for the potency of the endogenous fibrinolytic system. The vascular endothelium plays a pivotal role in its ability to produce and release t-PA [1,2], while the main source of plasma PAI-1 is the platelets [3,4]. The platelets retain high levels of mainly active PAI-1 [5]

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Discussion

Conclusion