title: Induction of hepatic cyclooxygenase-2 by hyperhomocysteinemia via nuclear factor-kappaB activation.
abstract: 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-kappaB in the same liver tissue in which COX-2 was induced. Administration of a NF-kappaB 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 IkappaBalpha leading to NF-kappaB activation in the liver. Administration of 4-hydroxy-tetramethyl-piperidine-1-oxyl, an SOD mimetic, to hyperhomocysteinemic rats not only inhibited NF-kappaB 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-kappaB activation. Increased oxidative stress and inflammatory response may contribute to liver injury associated with hyperhomocysteinemia.
authors: St Boniface Hospital Research Centre, Winnipeg, Canada.
authors: Nan
authors: N
authors: Wu
authors: Yaw L
authors: YL
authors: Siow
authors: Karmin
authors: K
authors: O
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004790:Enzyme Induction; D006505:Hepatitis / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D011759:Pyrrolidines; D012333:RNA, Messenger; D013113:Spin Labels; D013859:Thiocarbamates; D006710:Homocysteine; D013481:Superoxides; D000072000:NF-KappaB Inhibitor alpha; C020972:pyrrolidine dithiocarbamic acid; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C001803:tempol