Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300

Abstract

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)E generation in the murine vasculature and in human vascular smooth muscle cells. In line with this, the expression of the key enzyme for PGE 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.

Chronic Treatment with Fluoxetine Induces Sex-Dependent Analgesic Effects and Modulates HDAC2 and mGlu2 Expression in Female Mice

“…A number of HDAC inhibitors have been tested in different pain models and it has been shown that they have analgesic effects through different mechanisms ( Chiechio et al, 2009 , 2010 ; Bai et al, 2010 ; Zhang et al, 2011 ; Denk et al, 2013 ; Matsushita et al, 2013 ; Onofrj et al, 2013 ; Ximenes et al, 2013 ; Chen et al, 2014 ; Kukkar et al, 2014 ; Zammataro et al, 2014 ; Capasso et al, 2015 ; Cao et al, 2016 ; Tao et al, 2016 ; Alqinyah et al, 2017 ; Fork et al, 2017 ; Lin et al, 2017 ). We first demonstrated that HDAC inhibitors have analgesic properties via the upregulation of the metabotropic glutamate receptor type-2 ( Chiechio et al, 2009 , 2010 ; Onofrj et al, 2013 ), an inhibitory receptor whose activation or upregulation mediates analgesia ( Chiechio et al, 2002 , 2009 , 2010 ; Onofrj et al, 2013 ; Zammataro et al, 2014 ; Chiechio, 2016 ).…”

Effects of ultrasound-guided erector spinae plane block on the immune function and postoperative recovery of patients undergoing radical mastectomy

“…When NPY is expressed in large quantities, it will participate in pain nerve transmission (18). High expression of PGE2 will reduce the pain threshold of patients and increase their subjective pain (19). 5-HT can centrally transmission pain signals through the cerebral cortex to produce pain (20).…”