文章基本信息

标题：Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300
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作者：Christian Fork ; Andrea E. Vasconez ; Patrick Janetzko 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2017
卷号：58
期号：2
页码：386-392
DOI：10.1194/jlr.M072280
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Nonsteroidal anti-inflammatory drugs are the most widely used medicine to treat pain and inflammation, and to inhibit platelet function. Understanding the expression regulation of enzymes of the prostanoid pathway is of great medical relevance. Histone acetylation crucially controls gene expression. We set out to identify the impact of histone deacetylases (HDACs) on the generation of prostanoids and examine the consequences on vascular function. HDAC inhibition (HDACi) with the pan-HDAC inhibitor, vorinostat, attenuated prostaglandin (PG)E₂ generation in the murine vasculature and in human vascular smooth muscle cells. In line with this, the expression of the key enzyme for PGE₂ synthesis, microsomal PGE synthase-1 (PTGES1), was reduced by HDACi. Accordingly, the relaxation to arachidonic acid was decreased after ex vivo incubation of murine vessels with HDACi. To identify the underlying mechanism, chromatin immunoprecipitation (ChIP) and ChIP-sequencing analysis were performed. These results suggest that HDACs are involved in the recruitment of the transcriptional activator p300 to the PTGES1 gene and that HDACi prevented this effect. In line with the acetyltransferase activity of p300, H3K27 acetylation was reduced after HDACi and resulted in the formation of heterochromatin in the PTGES1 gene. In conclusion, HDAC activity maintains PTGES1 expression by recruiting p300 to its gene.
关键词：epigenetics ; prostaglandins ; prostaglandin E₂ ; vascular biology ; smooth muscle cells ; histone deacetylase