title: Partial deletion of argininosuccinate synthase protects from pyrazole plus lipopolysaccharide-induced liver injury by decreasing nitrosative stress.
abstract: Argininosuccinate synthase (ASS) is the rate-limiting enzyme in the urea cycle. Along with nitric oxide synthase (NOS)-2, ASS endows cells with the L-citrulline/nitric oxide (NO·) salvage pathway to continually supply L-arginine from L-citrulline for sustained NO· generation. Because of the relevant role of NOS in liver injury, we hypothesized that downregulation of ASS could decrease the availability of intracellular substrate for NO· synthesis by NOS-2 and, hence, decrease liver damage. Previous work demonstrated that pyrazole plus LPS caused significant liver injury involving NO· generation and formation of 3-nitrotyrosine protein adducts; thus, wild-type (WT) and Ass+/- mice (Ass+/+ mice are lethal) were treated with pyrazole plus LPS, and markers of nitrosative stress, as well as liver injury, were analyzed. Partial ablation of Ass protected from pyrazole plus LPS-induced liver injury by decreasing nitrosative stress and hepatic and circulating TNFα. Moreover, apoptosis was prevented, since pyrazole plus LPS-treated Ass+/- mice showed decreased phosphorylation of JNK; increased MAPK phosphatase-1, which is known to deactivate JNK signaling; and lower cleaved caspase-3 than treated WT mice, and this was accompanied by less TdT-mediated dUTP nick end labeling-positive staining. Lastly, hepatic neutrophil accumulation was almost absent in pyrazole plus LPS-treated Ass+/- compared with WT mice. Partial Ass ablation prevents pyrazole plus LPS-mediated liver injury by reducing nitrosative stress, TNFα, apoptosis, and neutrophil infiltration.
authors: Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors: Yongke
authors: Y
authors: Lu
authors: Tung Ming
authors: TM
authors: Leung
authors: Stephen C
authors: SC
authors: Ward
authors: Natalia
authors: N
authors: Nieto
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D015538:Nitrosation / Q000187:drug effects* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D011506:Proteins; D011720:Pyrazoles; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C031280:pyrazole; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C505409:Casp3 protein, mouse; D053148:Caspase 3; D001124:Argininosuccinate Synthase