title: Thioredoxin glycation: A novel posttranslational modification that inhibits its antioxidant and organ protective actions.
abstract: Thioredoxin (Trx) is an antioxidant and antiapoptotic molecule, and its activity is regulated by posttranslational modifications. Trx-1 has recently been reported to exert potent protective action against endotoxic liver injury. However, whether Trx-1 activity is affected by endotoxin has never been previously investigated. The aim of the present study was to determine endotoxic regulation of Trx-1, and the potential mechanism involved. In vitro coincubation of Trx-1 with lipopolysaccharide (LPS) inhibited Trx-1 activity in a dose- and time-dependent fashion. The core (polysaccharide containing) region of LPS had a greater inhibitory effect on Trx-1 activity than its Lipid A fragment, suggesting the involvement of sugar groups. Periodic acid-Schiff staining and fructosamine assay demonstrated that Trx-1 was rapidly glycated by LPS. Aminoguanidine, a competitive glycation-inhibitor, completely blocked the inhibitory effect of LPS on Trx-1. Moreover, Trx-1 activity was also significantly inhibited by in vitro ribose incubation. Finally, in vivo administration of Trx-1, but not glycated Trx-1, reduced LPS-induced hepatic injury. Taken together, these results demonstrated for the first time that Trx-1 is susceptible to glycative inactivation. This novel posttranslational Trx-1 modification contributes to LPS cytotoxicity, suggesting that blockading protein glycation might be a new therapeutic strategy against endotoxic organ injury.
authors.affiliation: Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Philadelphia, PA 19107, USA.
authors.forename: Yuexing
authors.initials: Y
authors.lastname: Yuan
authors.forename: Xiangying
authors.initials: X
authors.lastname: Jiao
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.forename: Yajing
authors.initials: Y
authors.lastname: Wang
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Christopher
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Lopez
authors.forename: Satish P
authors.initials: SP
authors.lastname: Ramachandrarao
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D011499:Protein Processing, Post-Translational; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D006146:Guanidines; D008070:Lipopolysaccharides; D013879:Thioredoxins; C004479:pimagedine