6533b823fe1ef96bd127e2ba
RESEARCH PRODUCT
Extracellular histones disarrange vasoactive mediators reléase through COX-NOS interaction in human endothelial cells
Daniel Pérez-cremadesCarlos Bueno-betíFederico V. PallardóFederico V. PallardóSusana NovellaCarlos EhermenegildoJosé Luis García-jiménezJosé Luis García-giménezJosé Santiago Ibáñez-cabellosJosé Santiago Ibáñez-cabellossubject
0301 basic medicineProstacyclinHistoneschemistry.chemical_compoundThromboxane A2Cytochrome P-450 Enzyme SystemSuperoxidesEnosvascular mediatorsGenètica humanabiologySuperoxideendothelial cellsIntramolecular OxidoreductasesEndothelial stem cellMolecular MedicineOriginal ArticleThromboxane-A SynthaseSignal Transductionmedicine.drugmedicine.medical_specialtyNitric Oxide Synthase Type IIIPrimary Cell CultureNitric OxideProstacyclin synthaseNitric oxideCyclic N-OxidesThromboxane A203 medical and health sciencesInternal medicineHuman Umbilical Vein Endothelial CellsmedicineExtracellularHumansRNA MessengerprostanoidsDose-Response Relationship DrugOriginal ArticlesCell Biologybiology.organism_classificationEpoprostenolÒxid nítric030104 developmental biologyEndocrinologyGene Expression RegulationchemistryCelecoxibCyclooxygenase 2Cyclooxygenase 1biology.proteinSpin LabelsProteïnesextracellular histonesdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-01-01 |