1. Inflammation-mediated deacetylation of the ribonuclease 1 promoter via histone deacetylase 2 in endothelial cells.
- Author
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Bedenbender K, Scheller N, Fischer S, Leiting S, Preissner KT, Schmeck BT, and Vollmeister E
- Subjects
- Benzamides pharmacology, Cells, Cultured, Chromatin genetics, Chromatin metabolism, Chromatin Immunoprecipitation, Gene Knockdown Techniques, Histone Deacetylase 1 antagonists & inhibitors, Histone Deacetylase 1 genetics, Histone Deacetylase 1 metabolism, Histone Deacetylase 2 antagonists & inhibitors, Histone Deacetylase 2 genetics, Histone Deacetylase Inhibitors pharmacology, Human Umbilical Vein Endothelial Cells drug effects, Humans, Inflammation Mediators metabolism, Promoter Regions, Genetic, Pyridines pharmacology, RNA, Messenger genetics, RNA, Messenger metabolism, Ribonuclease, Pancreatic metabolism, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha pharmacology, Histone Deacetylase 2 metabolism, Human Umbilical Vein Endothelial Cells metabolism, Ribonuclease, Pancreatic genetics
- Abstract
Ribonuclease 1 (RNase1) is a circulating extracellular endonuclease that regulates the vascular homeostasis of extracellular RNA and acts as a vessel- and tissue-protective enzyme. Upon long-term inflammation, high amounts of proinflammatory cytokines affect endothelial cell (EC) function by down-regulation of RNase1. Here, we investigated the transcriptional regulation of RNase1 upon inflammation in HUVECs. TNF-α or IL-1β stimulation reduced the expression of RNase1 relative to the acetylation state of histone 3 at lysine 27 and histone 4 of the RNASE1 promoter. Inhibition of histone deacetylase (HDAC) 1, 2, and 3 by the specific class I HDAC inhibitor MS275 abolished the TNF-α- or IL-1β-mediated effect on the mRNA and chromatin levels of RNase1. Moreover, chromatin immunoprecipitation kinetics revealed that HDAC2 accumulates at the RNASE1 promoter upon TNF-α stimulation, indicating an essential role for HDAC2 in regulating RNase1 expression. Thus, proinflammatory stimulation induced recruitment of HDAC2 to attenuate histone acetylation at the RNASE1 promoter site. Consequently, treatment with HDAC inhibitors may provide a new therapeutic strategy to stabilize vascular homeostasis in the context of inflammation by preventing RNase1 down-regulation in ECs.-Bedenbender, K., Scheller, N., Fischer, S., Leiting, S., Preissner, K. T., Schmeck, B. T., Vollmeister, E. Inflammation-mediated deacetylation of the ribonuclease 1 promoter via histone deacetylase 2 in endothelial cells.
- Published
- 2019
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