title: Inhibition of arginase ameliorates experimental ulcerative colitis in mice.
abstract: Nitric oxide (NO) is produced from the conversion of L-arginine by NO synthase (NOS) and regulates a variety of processes in the gastrointestinal tract. Considering the increased activity of arginase in colitis tissue, it is speculated that arginase could inhibit NO synthesis by competing for the same L-arginine substrate, resulting in the exacerbation of colitis. We examined the role of arginase and its relationship to NO metabolism in dextran sulfate sodium (DSS)-induced colitis. Experimental colitis was induced in mice by administration of 2.5% DSS in drinking water for 8 days. Treatment for arginase inhibition was done by once daily intraperitoneal injection of N(ω)-hydroxy-nor- arginine (nor-NOHA). On day 8, we evaluated clinical parameters (body weight, disease activity index, and colon length), histological features, the activity and expression of arginase, L-arginine content, the expression of NO synthase (NOS), and the concentration of NO end-product (NOx: nitrite + nitrate). Administration of nor-NOHA improved the worsened clinical parameters and histological features in DSS-induced colitis. Treatment with nor-NOHA attenuated the increased activity of arginase, upregulation of arginase Ι at both mRNA and protein levels, and decreased the content of L-arginine in colonic tissue in the DSS-treated mice. Conversely, despite the decreased expression of NOS2 mRNA, the decreased concentration of NOx in colonic tissues was restored to almost normal levels. The consumption of L-arginine by arginase could lead to decreased production of NO from NOS, contributing to the pathogenesis of the colonic inflammation; thus, arginase inhibition might be effective for improving colitis.
authors.affiliation: Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences ,  Okayama ,  Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Akazawa
authors.forename: M
authors.initials: M
authors.lastname: Kubo
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: F
authors.initials: F
authors.lastname: Yan
authors.forename: H
authors.initials: H
authors.lastname: Setiawan
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Fujikura
authors.forename: K
authors.initials: K
authors.lastname: Ogino
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D007527:Isoenzymes; C404735:N(omega)-hydroxynorarginine; D012333:RNA, Messenger; D009569:Nitric Oxide; D016264:Dextran Sulfate; D001120:Arginine; C544448:Arg1 protein, mouse; D001119:Arginase