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Am J Physiol Regul Integr Comp Physiol 297: R1086-R1094, 2009. First published August 5, 2009; doi:10.1152/ajpregu.00293.2009
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Articles

Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-{kappa}B activation

Nan Wu,1,3 Yaw L. Siow,1,3,4 and Karmin O1,2,3

1St. Boniface Hospital Research Centre, Winnipeg, Canada; Departments of 2Animal Science and 3Physiology, University of Manitoba, Mannitoba, Canada; and 4Agriculture and Agri-Food Canada

Submitted May 26, 2009 ; accepted in final form August 4, 2009

Hyperhomocysteinemia, an elevation of blood homocysteine (Hcy), 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 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-{kappa}B in the same liver tissue in which COX-2 was induced. Administration of a NF-{kappa}B 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{kappa}B{alpha} leading to NF-{kappa}B activation in the liver. Administration of 4-hydroxy-tetramethyl-piperidine-1-oxyl, an SOD mimetic, to hyperhomocysteinemic rats not only inhibited NF-{kappa}B 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-{kappa}B activation. Increased oxidative stress and inflammatory response may contribute to liver injury associated with hyperhomocysteinemia.

homocysteine; oxidative stress; inflammatory response; liver injury


Address for reprint requests and other correspondence: K. O, Integrative Biology Laboratory, St. Boniface Hospital Research Centre, 351 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6 (e-mail: karmino{at}sbrc.ca).






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