title: Extracellular histones disarrange vasoactive mediators release through a COX-NOS interaction in human endothelial cells.
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.
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.|INCLIVA Biomedical Research Institute, Valencia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pérez-Cremades
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.|INCLIVA Biomedical Research Institute, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueno-Betí
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.|INCLIVA Biomedical Research Institute, Valencia, Spain.|Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: García-Giménez
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.|INCLIVA Biomedical Research Institute, Valencia, Spain.|Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain.
authors.forename: José Santiago
authors.initials: JS
authors.lastname: Ibañez-Cabellos
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.|INCLIVA Biomedical Research Institute, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Hermenegildo
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.|INCLIVA Biomedical Research Institute, Valencia, Spain.|Center for Biomedical Network Research on Rare Diseases (CIBERER), Institute of Health Carlos III, Valencia, Spain.
authors.forename: Federico V
authors.initials: FV
authors.lastname: Pallardó
authors.affiliation: Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.|INCLIVA Biomedical Research Institute, Valencia, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Novella
mesh_terms: D000068579:Celecoxib / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000819:agonists* / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006657:Histones / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013113:Spin Labels; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D003497:Cyclic N-Oxides; D006657:Histones; D012333:RNA, Messenger; D013113:Spin Labels; D013481:Superoxides; D009569:Nitric Oxide; D013928:Thromboxane A2; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase; D000068579:Celecoxib; C001803:tempol
keywords: endothelial cells; extracellular histones; nitric oxide; prostanoids; vascular mediators