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

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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

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Abstract

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

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Entinostat	Histone deacetylase (Protein Group)	Protein group	Humans	Yes	Inhibitor	Details