title: Aggravation of post-ischemic liver injury by overexpression of insulin-like growth factor binding protein 3.
abstract: Insulin-like growth factor-1 (IGF-1) is known to inhibit reperfusion-induced apoptosis. IGF-binding protein-3 (IGFBP-3) is the major circulating carrier protein for IGF-1 and induces apoptosis. In this study, we determined if IGFBP-3 was important in the hepatic response to I/R. To deliver IGFBP-3, we used an adenovirus containing IGFBP-3 cDNA (AdIGFBP-3) or an IGFBP-3 mutant devoid of IGF binding affinity but retaining IGFBP-3 receptor binding ability (AdIGFBP-3(GGG)). Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Protein levels of IGFBP-3 were increased after reperfusion and showed a positive correlation with the extent of liver injury. Prior injection with AdIGFBP-3 aggravated liver injury: serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration were markedly increased compared to control mice. A decrease in antioxidant potential and an upregulation of NADPH oxidase might have caused these aggravating effects of IGFBP-3. Experiments using HepG2 cells and N-acetylcysteine-pretreated mice showed a discernible effect of IGFBP-3 on reactive oxygen species generation. Lastly, AdIGFBP-3 abolished the beneficial effects of ischemic preconditioning and hypothermia. Mice treated with AdIGFBP-3(GGG) exhibited effects similar to those of AdIGFBP-3, suggesting a ligand-independent effect of IGFBP-3. Our results suggest IGFBP-3 as an aggravating factor during hepatic I/R injury.
authors.affiliation: 1] Department of Sports Medicine, Taishan Medical University, Taian, Shandong, 271-000, China [2] Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, 561-756, Republic of Korea.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, 561-756, Republic of Korea.
authors.forename: Hyoung-Won
authors.initials: HW
authors.lastname: Koh
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, 561-756, Republic of Korea.
authors.forename: Ui-Jin
authors.initials: UJ
authors.lastname: Bae
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Jeonbuk, 561-756, Republic of Korea.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001219:Aspartate Aminotransferases / Q000097:blood; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D056945:Hep G2 Cells; D006801:Humans; D007036:Hypothermia, Induced; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D019194:Ischemic Preconditioning; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020556:Neutrophil Infiltration / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D016166:Free Radical Scavengers; D018972:Insulin-Like Growth Factor Binding Protein 3; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000111:Acetylcysteine