Histone deacetylase inhibitors stimulate tissue-type plasminogen activator production in vascular endothelial cells.
J Thromb Thrombolysis
; 35(2): 185-92, 2013 Feb.
Article
em En
| MEDLINE
| ID: mdl-23229086
ABSTRACT
A reduced capacity for acute tissue-type plasminogen activator (t-PA) release is likely to be associated with an impaired endogenous defense against intravascular thrombosis. Efficient approaches to pharmacologically restore a defective t-PA release have been lacking, but recent observations suggest that histone deacetylase inhibitors (HDACis) enhance t-PA production in vitro. HDACis have diverse chemical structures and different HDAC-enzyme sub-class targeting. We here compared the effects of several clinically used HDACis on t-PA production in endothelial cells. Human umbilical vein endothelial cells were exposed to a panel of 11 different HDACis and t-PA mRNA and protein levels were quantified. All HDACis dose-dependently stimulated t-PA mRNA and protein expression with similar maximal efficacy but with different potencies. Already at low concentrations, the majority of inhibitors caused significant and sustained effects on t-PA production. In addition, selected HDACis were capable of normalizing t-PA production when suppressed by the inflammatory cytokine TNF-α. We conclude that HDACis targeting classical HDAC enzymes are powerful inducers of t-PA expression in cultured endothelial cells and could be promising candidates for pharmacological modulation of endogenous fibrinolysis in man.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação para Cima
/
Ativador de Plasminogênio Tecidual
/
Células Endoteliais
/
Inibidores de Histona Desacetilases
/
Células Endoteliais da Veia Umbilical Humana
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article