title: Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages.
abstract: Folic acid supplementation is a promising approach for patients with cardiovascular diseases associated with hyperhomocysteinemia. We have demonstrated that homocysteine (Hcy) activates nuclear factor-kappaB (NF-kappaB), a transcription factor that plays an important role in inflammatory responses. The aim of the present study was to investigate the effect of folic acid on Hcy-induced NF-kappaB activation in macrophages. Hcy treatment (100 micromol/L) resulted in NF-kappaB activation and increased monocyte chemoattractant protein-1 (MCP-1) expression in THP-1 derived macrophages. Hcy-induced NF-kappaB activation was associated with a significant increase in the intracellular superoxide anion levels. There was a significant increase in phosphorylation and membrane translocation of NADPH oxidase p47phox subunit in Hcy-treated cells. Addition of folic acid (200 ng/mL) to the culture medium abolished NADPH oxidase-dependent superoxide anion generation in macrophages by preventing phosphorylation of p47phox subunit. Consequently, Hcy-induced NF-kappaB activation and MCP-1 expression was inhibited. Such an inhibitory effect of folic acid was independent of its Hcy-lowering ability. Taken together, these results suggest that folic acid treatment can effectively inhibit Hcy-induced oxidative stress and inflammatory responses in macrophages. This may represent one of the mechanisms by which folic acid supplementation exerts a protective effect in cardiovascular disorders.
authors.affiliation: Department of Animal Science, University of Manitoba, National Centre for Agri-Food Research in Medicine, Laboratory of Integrative Biology, NCARM, St Boniface Hospital Research Centre, Winnipeg, Canada.
authors.forename: Kathy K W
authors.initials: KK
authors.lastname: Au-Yeung
authors.forename: Johnny C W
authors.initials: JC
authors.lastname: Yip
authors.forename: Yaw L
authors.initials: YL
authors.lastname: Siow
authors.forename: Karmin
authors.initials: K
authors.lastname: O
mesh_terms: D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005492:Folic Acid / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; D012333:RNA, Messenger; D006710:Homocysteine; D013481:Superoxides; D005492:Folic Acid; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1