Influence of proinflammatory stimuli on the expression of vascular ribonuclease 1 in endothelial cells

Abstract

Extracellular RNA (eRNA) released under injury or pathological conditions has been identified as a yet unrecognized vascular alarm signal to induce procoagulant, permeability-promoting, and proinflammatory activities. eRNA-induced functions were largely prevented by administration of RNase1 as a natural blood vessel-protective antagonist of eRNA. The aim of this study was to investigate the inflammatory regulation of endothelial cell RNase1, which is partly stored in Weibel-Palade bodies of these cells. Long-term treatment of human umbilical vein endothelial cells (HUVECs) with inflammatory agents like tumor necrosis factor α (TNF-α) or interleukin 1β (IL-1β), but not with eRNA, significantly decreased the release (34 ± 5%; 34 ± 7% of control) as well as the cellular expression (19.5 ± 5%; 33 ± 8% of control) of RNase1. Down-regulation of RNase1 by TNF-α stimulation or RNase1 siRNA knockdown increased the permeability of HUVEC monolayers, demonstrated by dearrangement of VE-cadherins at cell-cell borders. Mechanistically, cytokine-induced decrease of RNase1 expression did not involve the nuclear factor κ B (NFκB) signaling pathway but epigenic modifications. Since inhibition of histone deacetylases resulted in recovery of RNase1 expression and secretion after cytokine treatment, an acetylation-dependent process of RNase1 regulation is proposed. These results indicate that cytokine-mediated down-regulation of RNase1 in endothelial cells may aggravate eRNA-induced inflammatory activities and thereby disturbs the vascular homeostasis of the extracellular RNA/RNase system.

Changes in brain ribonuclease (BRB) messenger RNA in granulosa cells (GCs) of dominant vs subordinate ovarian follicles of cattle and the regulation of BRB gene expression in bovine GCs

“…Similarly, Gansler et al [18] found that TNFα decreases RNase1 production by human umbilical vein endothelial cells. In contrast, Etoh et al [54] found that TNFα induced RNase5 mRNA expression in human colon cancer cells.…”

“…For example, tumor necrosis factor-α (TNFα) decreases RNase1 production by human umbilical vein endothelial cells [18]. Although TNFα inhibits basal and FSH-induced steroidogenesis in granulosa cells (GC) and is thought to play a role in the regulation of ovarian function [19, 20], the effect of TNFα on ovarian BRB production is unknown.…”

Targeting of Extracellular RNA Reduces Edema Formation and Infarct Size and Improves Survival After Myocardial Infarction in Mice

“…Concurrently, the intrinsic RNase activity was increased following MI, possibly as a direct response to the release of eRNA following myocardial injury or via eRNA‐induced inflammatory stimuli,22 as eRNA has been reported to induce RNase release from endothelial cells in vitro following inflammatory stimulation. The eRNA was measured in platelet‐free plasma and may be released by different sources including necrotic cells, apoptotic cells, or activated platelets at the sites of injury.…”

Extracellular Ribonucleic Acids (RNA) Enter the Stage in Cardiovascular Disease

“…19 Long-term treatment (for several hours) of endothelial cells with proinflammatory cytokines, such as TNF-α or IL-1β, results in significant downregulation of RNase1-mRNA and RNase1-protein levels, mainly involving epigenetic regulation of histone modifications. 96 This indicates that acute inflammatory conditions promote a temporary RNase1 release to degrade the excess of proinflammatory eRNA, whereas chronic stimulatory conditions lead to a decreased RNase1 production, thereby providing another regulatory aspect of the vascular eRNA/RNase system. In which way extracellular miRNAs are affected by changes in circulating RNase1 concentrations remains to be analyzed.…”

“…19,96,97 Also after acute myocardial infarction, serum RNase activity was described to increase at 1 day, peaking at 3 to 5 days and returning to baseline at 14 weeks after injury, compared with healthy controls. 98 In experimental atherosclerosis in Ldlr −/− mice, a biphasic characteristic of RNase activity was observed with a temporary increase during the first 2 weeks, followed by a significant and sustained decrease to ≈20% to 40% of the activity in baseline controls, starting at 4 weeks of HFD feeding throughout the 36 weeks of the observation period.…”