Induction of Hepatic Cyclooxygenase-2 by Hyperhomocysteinemia via Nuclear Factor kappa-B Activation. American journal of physiology. Regulatory, integrative and comparative physiology [Am J Physiol Regul Integr Comp Physiol] Journal article | | Title | Induction of Hepatic Cyclooxygenase-2 by Hyperhomocysteinemia via Nuclear Factor kappa-B Activation. | | Author(s) | Wu N, Siow YL, O K | | Institution | St. Boniface Hospital Research Centre. | | Source | Am J Physiol Regul Integr Comp Physiol 2009 Aug 5. | | Abstract | Hyperhomocysteinemia, an elevation of blood homocysteine (tHcy), is a metabolic disorder associated with dysfunction of multiple organs. Apart from endothelial dysfunction, Hcy can cause hepatic lipid accumulation and liver injury. However, the mechanism responsible for Hcy-induced liver injury is poorly understood. 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 week or 4 weeks. Serum and liver concentrations of Hcy were significantly elevated after 1 week or 4 weeks 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-week hyperhomocysteinemic rats than that in 4-week group. Electrophoretic mobility shift assay revealed an activation of NF-kB in the same liver tissue in which COX-2 was induced. Administration of a NF-kB 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 IkB-alpha leading to NF-kB activation in the liver. Administration of 4-hydroxy-tetramethyl-piperidine-1-oxyl (TEMPO), a superoxide dismutase mimetic, to hyperhomocysteinemic rats not only inhibited NF-kB 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-kB activation. Increased oxidative stress and inflammatory response may contribute to liver injury associated with hyperhomocysteinemia. Key words: homocysteine, cyclooxygenase-2, oxidative stress, inflammatory response. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19657099 |
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