Epigenetic control of tissue-type plasminogen activator synthesis in human endothelial cells.

Article Details


Dunoyer-Geindre S, Kruithof EK

Epigenetic control of tissue-type plasminogen activator synthesis in human endothelial cells.

Cardiovasc Res. 2011 Jun 1;90(3):457-63. doi: 10.1093/cvr/cvr028. Epub 2011 Jan 31.

PubMed ID
21282301 [ View in PubMed

AIMS: Tissue-type plasminogen activator (t-PA) is produced by endothelial cells (EC) and is responsible for the removal of intravascular fibrin deposits. We investigated whether expression of t-PA by EC is under epigenetic control. METHODS AND RESULTS: Methylation analysis of the proximal t-PA promoter revealed a stretch of unmethylated CpG dinucleotides from position -121 to +59, while upstream CpG dinucleotides were all methylated. In contrast, in human primary hepatocytes, which express t-PA at much lower levels than EC, the proximal promoter was partially methylated. Treatment of EC with the non-specific histone deacetylase (HDAC) inhibitors butyrate and trichostatin and with MS275, a specific inhibitor of class I HDAC, resulted in a time- and dose-dependent increase in t-PA expression. Garcinol and anacardic acid, inhibitors of the histone acetyl transferases CBP/p300 and PCAF, reduced basal and HDAC inhibitor-induced t-PA expression, whereas curcumin, an inhibitor of CBP/p300 only, had no effect. We performed chromosome immunoprecipitation analysis of the t-PA promoter using antibodies specific for acetylated histone H3 or H4 and observed an increase in H3 acetylation of 10 +/- 3 and 44 +/- 14-fold in EC treated with trichostatin or MS275, respectively, and in H4 acetylation of 7.7 +/- 1.4 and 16 +/- 3-fold, respectively. CONCLUSION: The proximal t-PA promoter is unmethylated in human EC and partially methylated in human primary hepatocytes. Expression of t-PA by EC is repressed by HDACs in a mechanism that involves de-acetylation of histone H3 and H4.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
EntinostatHistone deacetylase (Protein Group)Protein groupHumans