Superoxide limits cyclosporine-A-induced formation of peroxynitrite in endothelial cells(2).
Peroxynitrite (ONOO(-)) is a potent oxidant formed by the nonenzymatic reaction between superoxide anion (O(2)(*-)) and nitric oxide (NO*) in a one-to-one stoichiometry. Accumulated evidence suggests that endothelial dysfunction coincides with an enhanced NO* synthase expression and O(2)(*-) production, facilitating ONOO(-) formation. In vivo, formation of ONOO(-) has been associated with atherosclerosis and vascular aging. The immunosuppressor Cyclosporine A (CsA) has been associated to human endothelial dysfunction and accelerated atherosclerosis. We have previously shown that CsA induced a transcriptionally mediated increase of the eNOS gene expression and that CsA induced the formation of nitric oxide, O(2)(*-), and ONOO(-) in vascular endothelial cells. In this work, we evaluate the CsA-induced relative amounts of formation of O(2)(*-) and NO*, providing data consistent with a role of O(2)(*-), and not NO*, as the limiting factor in the CsA-dependent intracellular formation of ONOO(-) in vascular endothelial cells. Furthermore, when endothelial cells were treated with CsA in a situation of increased generation of superoxide such as that provided by high glucose levels, a further increase in the formation of peroxynitrite was detected. The temporal availability of O(2)(*-) for peroxynitrite formation may thus become critical in the pathophysiological scenarios where reactive nitrogen intermediates are operative.
Navarro-Antolín
Javier
J
Centro de Investigaciones Biológicas and Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain.
López-Muñoz
María José
MJ
Soria
Javier
J
Lamas
Santiago
S
D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D007124:Immunoenzyme Techniques; D013058:Mass Spectrometry; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D013481:Superoxides / Q000378:metabolism*
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009573:Nitrites; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D016572:Cyclosporine; D005947:Glucose