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Göteborgs universitets publikationer

Role of histone acetylation in the stimulatory effect of valproic acid on vascular endothelial tissue-type plasminogen activator expression

Författare och institution:
Pia Larsson (Institutionen för medicin, avdelningen för molekylär och klinisk medicin); Erik Ulfhammer (Institutionen för medicin, avdelningen för molekylär och klinisk medicin); Mia Magnusson (Institutionen för medicin, avdelningen för molekylär och klinisk medicin); Niklas Bergh (Institutionen för medicin, avdelningen för molekylär och klinisk medicin); S. Lunke (-); A. El-Osta (-); R. L. Medcalf (-); Per-Arne Svensson (Institutionen för medicin, avdelningen för molekylär och klinisk medicin); Lena Karlsson (Institutionen för medicin, avdelningen för molekylär och klinisk medicin); Sverker Jern (Institutionen för medicin, avdelningen för molekylär och klinisk medicin)
Publicerad i:
PloS one, 7 ( 2 ) s. e31573
ISSN:
1932-6203
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2012
Språk:
engelska
Fulltextlänk:
Sammanfattning (abstract):
AIMS: 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. METHODS AND 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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Klinisk medicin
Postens nummer:
157841
Posten skapad:
2012-05-21 14:08
Posten ändrad:
2016-06-10 11:44

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