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The aim of this study was to investigate the regulation of cyclooxygenase-2 (COX-2), a proinflammatory factor, expression in the liver during the initial phase of hyperhomocysteinemia. Sprague-Dawley rats were fed a high-methionine diet for 1 or 4 wk. Serum and liver concentrations of Hcy were significantly elevated after 1 or 4 wk of dietary treatment. COX-2 mRNA and protein levels were significantly elevated in the liver of hyperhomocysteinemic rats. The induction of COX-2 expression was more prominent in 1-wk hyperhomocysteinemic rats than that in the 4-wk group. EMSA revealed an activation of NF-\u03baB in the same liver tissue in which COX-2 was induced. Administration of a NF-\u03baB inhibitor to hyperhomocysteinemic rats effectively abolished hepatic COX-2 expression, inhibited the formation of inflammatory foci, and improved liver function. Further investigation revealed that oxidative stress due to increased superoxide generation was responsible for increased phosphorylation and degradation of I\u03baB\u03b1 leading to NF-\u03baB activation in the liver. Administration of 4-hydroxy-tetramethyl-piperidine-1-oxyl, an SOD mimetic, to hyperhomocysteinemic rats not only inhibited NF-\u03baB activation but also prevented hepatic COX-2 induction and improved liver function. These results suggest that hyperhomocysteinemia-induced COX-2 expression is mediated via NF-\u03baB activation. Increased oxidative stress and inflammatory response may contribute to liver injury associated with hyperhomocysteinemia.<\/jats:p>","DOI":"10.1152\/ajpregu.00293.2009","type":"journal-article","created":{"date-parts":[[2009,8,6]],"date-time":"2009-08-06T01:46:41Z","timestamp":1249523201000},"page":"R1086-R1094","source":"Crossref","is-referenced-by-count":20,"title":["Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-\u03baB activation"],"prefix":"10.1152","volume":"297","author":[{"given":"Nan","family":"Wu","sequence":"first","affiliation":[{"name":"St. Boniface Hospital Research Centre, Winnipeg, Canada;"},{"name":"Physiology, University of Manitoba, Mannitoba, Canada; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaw L.","family":"Siow","sequence":"additional","affiliation":[{"name":"St. Boniface Hospital Research Centre, Winnipeg, Canada;"},{"name":"Physiology, University of Manitoba, Mannitoba, Canada; 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