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

Published on Jan 31, 2011in Cardiovascular Research8.168
· DOI :10.1093/CVR/CVR028
Sylvie Dunoyer-Geindre16
Estimated H-index: 16
(Geneva College),
Egbert K. O. Kruithof41
Estimated H-index: 41
(Geneva College)
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 pos- ition 2121 to +59, while upstream CpG dinucleotides were all methylated. In contrast, in human primary hepato- cytes, 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.
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