Abstract
Extracellular histones are mediators of inflammation, tissue injury and organ dysfunction. Interactions between circulating histones and vascular endothelial cells are key events in histone‐mediated pathologies. Our aim was to investigate the implication of extracellular histones in the production of the major vasoactive compounds released by human endothelial cells (HUVECs), prostanoids and nitric oxide (NO). HUVEC exposed to increasing concentrations of histones (0.001 to 100 μg/ml) for 4 hrs induced prostacyclin (PGI2) production in a dose‐dependent manner and decreased thromboxane A2 (TXA2) release at 100 μg/ml. Extracellular histones raised cyclooxygenase‐2 (COX‐2) and prostacyclin synthase (PGIS) mRNA and protein expression, decreased COX‐1 mRNA levels and did not change thromboxane A2 synthase (TXAS) expression. Moreover, extracellular histones decreased both, eNOS expression and NO production in HUVEC. The impaired NO production was related to COX‐2 activity and superoxide production since was reversed after celecoxib (10 μmol/l) and tempol (100 μmol/l) treatments, respectively. In conclusion, our findings suggest that extracellular histones stimulate the release of endothelial‐dependent mediators through an up‐regulation in COX‐2‐PGIS‐PGI2 pathway which involves a COX‐2‐dependent superoxide production that decreases the activity of eNOS and the NO production. These effects may contribute to the endothelial cell dysfunction observed in histone‐mediated pathologies.
Highlights
Recent studies indicate that histones mediate proinflammatory activity when are released into extracellular space [1]
The first objective of this work was to investigate the effect of extracellular histones on the endothelial production of vasoactive compounds, in particular the two main vascular prostanoids, PGI2 and thromboxane A2 (TXA2), and nitric oxide (NO)
Histone-treated human umbilical vein endothelial cell (HUVEC) showed an increment in PGI2 production in a dose-dependent manner
Summary
Recent studies indicate that histones mediate proinflammatory activity when are released into extracellular space [1] In this regard, high levels of circulating histones in plasma have been detected in traumaassociated injury [2], ischaemia–reperfusion injuries in kidney [3] liver [4] and sepsis [5, 6]. Endothelium participates in numerous regulatory functions and contributes to and is affected by inflammatory processes. It is involved in blood coagulation and fibrinolysis, immune response by modulation of leucocyte interactions with the vessel wall and regulation of vascular tone and blood pressure [7]. After pro-inflammatory stimuli, endothelium undergoes activation characterized by increased local blood flow, leakage of plasma-protein-rich fluid into the tissues and recruitment and activation of circulating leucocytes [8]
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