Ibuprofen protects human endothelial cell prostaglandin H synthase from hydrogen peroxide.
Human endothelial cells exposed to H2O2 demonstrate decreased prostacyclin (PGI2) synthesis due to decreased prostaglandin H synthase (PGH synthase) activity. We tested the hypothesis that PGH synthase activity could be protected from H2O2 by a reversible nonsteroidal anti-inflammatory drug. Experiments demonstrate that ibuprofen if present during H2O2 exposure, protects endothelial cell PGH synthase against the decrease in prostaglandin formation caused by H2O2. Additional studies demonstrated that decreasing arachidonic acid release from cell phospholipids during H2O2 exposure did not protect PGI2 synthesis following H2O2 exposure. In other experiments, ibuprofen did not chelate Fe2+ in a conformation that inhibited the reactivity of Fe2+. In addition, ibuprofen did not scavenge HO. However, we demonstrate that ibuprofen significantly protects purified PGH synthase cyclooxygenase activity from the effects of H2O2. The results confirm the hypothesis. These findings suggest that ibuprofen displaces oxidant species from the cyclooxygenase site of PGH synthase, thereby preventing oxidation of the functional groups important for PGH synthase activity.
Wessels
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DA
Department of Veterans Affairs Medical Center, University of Iowa, Iowa City 52242, USA.
Hempel
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D002478:Cells, Cultured; D004336:Drug Antagonism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004795:Enzyme Stability / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007052:Ibuprofen / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects* / Q000378:metabolism
D016877:Oxidants; D006861:Hydrogen Peroxide; D011451:Prostaglandin-Endoperoxide Synthases; D007052:Ibuprofen