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.