Extracellular histones disarrange vasoactive mediators release through a COX-NOS interaction in human endothelial cells.
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.
['Pérez-Cremades|Daniel|D|', 'Bueno-Betí|Carlos|C|', 'García-Giménez|José Luis|JL|', 'Ibañez-Cabellos|José Santiago|JS|', 'Hermenegildo|Carlos|C|', 'Pallardó|Federico V|FV|', 'Novella|Susana|S|']
D000068579:Celecoxib D003497:Cyclic N-Oxides D051545:Cyclooxygenase 1 D051546:Cyclooxygenase 2 D003577:Cytochrome P-450 Enzyme System D004305:Dose-Response Relationship, Drug D011464:Epoprostenol D005786:Gene Expression Regulation D006657:Histones D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D019746:Intramolecular Oxidoreductases D009569:Nitric Oxide D052250:Nitric Oxide Synthase Type III D061251:Primary Cell Culture D012333:RNA, Messenger D015398:Signal Transduction D013113:Spin Labels D013481:Superoxides D013928:Thromboxane A2 D013930:Thromboxane-A Synthase
extracellular histones endothelial cells prostanoids nitric oxide vascular mediators