title: 3-Hydroxyanthranilic acid, one of L-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells.
abstract: Heme oxygenase (HO)-1 is important in the vascular system, and its genetic or pharmacological induction in endothelium would be effective for the prevention and treatment of atherosclerosis. The naturally occurring antioxidant 3-hydroxyanthranilic acid (HA), one of l-tryptophan metabolites formed in vivo along the metabolic route known as the kynurenine pathway during inflammation or infection, was found to induce HO-1 expression and to stimulate nuclear translocation of NF-E2 related factor 2 (Nrf2) in human umbilical vein endothelial cells (HUVECs). Pre-treatment with HA inhibited the secretion of monocyte chemoattractant protein (MCP)-1, the expression of vascular cell adhesion molecule (VCAM)-1 and the activation of transcriptional nuclear factor (NF)-kappaB in HUVECs stimulated with tumor necrosis factor-alpha, the major pro-inflammatory cytokine causing endothelial inflammation. Interestingly, the observed anti-inflammatory effects of HA were mimicked by a HO-1 inducer, cobalt protoporphyrin, and bilirubin, one of HO-1 enzymatic products, but abolished in the presence of a HO-1 inhibitor, tin protoporphyrin. Based on our findings, we suggest that Nrf2-dependent HO-1 expression induced by HA inhibits MCP-1 secretion, VCAM-1 expression and NF-kappaB activation associated with vascular injury and inflammation in atherosclerosis.
authors.affiliation: Medicinal Resources Research Institute and Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Chonbug 570-749, Republic of Korea.
authors.forename: Hyun-Ock
authors.initials: HO
authors.lastname: Pae
authors.forename: Gi-Su
authors.initials: GS
authors.lastname: Oh
authors.forename: Bok-Soo
authors.initials: BS
authors.lastname: Lee
authors.forename: Joung-Sik
authors.initials: JS
authors.lastname: Rim
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Hun-Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D014364:Tryptophan / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000975:Antioxidants; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016166:Free Radical Scavengers; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D015095:3-Hydroxyanthranilic Acid; D014364:Tryptophan; D051547:Heme Oxygenase-1; D001663:Bilirubin