Oxidative alterations of cyclooxygenase during atherogenesis.
Nitric oxide (*NO) and eicosanoids are critical mediators of physiological and pathophysiological processes. They include inflammation and atherosclerosis. *NO production and eicosanoid synthesis become disrupted during atherosclerosis and thus, it is important to understand the mechanisms that may contribute to this outcome. We, and others, have shown that nitrogen oxide (NO(x)) species modulate cyclooxygenase (COX; also known as prostaglandin H(2) synthase) activity and alter eicosanoid production. We have determined that peroxynitrite (ONOO(-)) has multiple effects on COX activity. ONOO(-) can provide the peroxide tone necessary for COX activation, such that simultaneous exposure of COX to its arachidonic acid substrate and ONOO(-) results in increased eicosanoid production. Alternatively, in the absence of arachidonic acid, ONOO(-) can modify COX through nitration of an essential tyrosine residue (Tyr385) such that it is incapable of catalysis. In this regard, we have shown that COX nitration occurs in human atherosclerotic tissue and in aortic lesions from ApoE(-/-) mice kept on a high fat diet. Additionally, we have demonstrated that Tyr nitration in ApoE(-/-) mice is dependent on the inducible form of NO synthase (iNOS). Under conditions where ONOO(-) persists and arachidonic acid is not immediately available, the cell may try to correct the situation by responding to ONOO(-) and releasing arachidonic acid via a signaling pathway to favor COX activation. Other post-translational modifications of COX by NO(x) species include S-nitrosation of cysteine (Cys) residues (which may have an activating effect) and Cys oxidation. The central focus of this review will include a discussion of how NO(x) species alter COX activity at the molecular level and how these modifications may contribute to altered eicosanoid output during atherosclerosis and lesion development.
Upmacis
Rita K
RK
Center of Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, United States. rupmacis@med.cornell.edu
Deeb
Ruba S
RS
Hajjar
David P
DP
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D003545:Cysteine / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation; D006418:Heme / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D009589:Nitrogen Oxides; D030421:Peroxynitrous Acid; D016718:Arachidonic Acid; D009569:Nitric Oxide; D014443:Tyrosine; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D003545:Cysteine