Redox regulation of vascular prostanoid synthesis by the nitric oxide-superoxide system.
Oxygen is involved in cell signaling through oxygenases and oxidases and this applies especially for the vascular system. Nitric oxide (*NO) and epoxyarachidonic acids are P450-dependent monooxygenase products and prostacyclin is formed via cyclooxygenase and a heme-thiolate isomerase. The corresponding vasorelaxant mechanisms are counteracted by superoxide which not only traps *NO but through the resulting peroxynitrite blocks prostacyclin synthase by nitration of an active site tyrosine residue. In a model of septic shock, this leads to vessel constriction by activation of the thromboxane A2-prostaglandin endoperoxide H2 receptor. This sequence of events is part of endothelial dysfunction in which the activated vascular smooth muscle counteracts and regenerates vessel tone by cyclooxygenase-2-dependent prostacyclin synthesis. Peroxynitrite was found to activate cyclooxygenases by providing the peroxide tone at nanomolar concentrations. Such new insights into the control of vascular function have allowed us to postulate a concept of redox regulation in which a progressive increase of superoxide production by NADPH-oxidase, mitochondria, xanthine oxidase, and even uncoupled NO-synthase triggers a network of signals originating from an interaction of *NO with superoxide.
Bachschmid
Markus
M
University of Konstanz, Department of Biology, D-78457 Konstanz, Germany. markus.bachschmid@t-online.de
Schildknecht
Stefan
S
Ullrich
Volker
V
D000818:Animals; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry* / Q000502:physiology; D010084:Oxidation-Reduction; D011453:Prostaglandins / Q000096:biosynthesis*; D013481:Superoxides / Q000737:chemistry* / Q000378:metabolism
D011453:Prostaglandins; D013481:Superoxides; D009569:Nitric Oxide