Amelioration of oxidant stress by the defensin lysozyme.
Reactive oxidant species (ROS), products of normal metabolism, cause oxidant injury if they accumulate in pathological amounts. Lysozyme (LZ) contains an 18-amino acid domain that binds agents such as advanced glycation end products (AGE) that generate ROS. We examined whether endogenous LZ affected physiological, or baseline, antioxidant balance and provided protection against both acute and chronic oxidant injury, using paraquat and H2O2 as agents of acute injury and AGE for chronic injury. Hen egg LZ-Tg mice had threefold higher serum LZ levels and decreased baseline AGE levels in serum and liver. These findings were linked to an enhanced baseline systemic GSH-to-GSSG ratio. Baseline levels of stress response genes p66(Shc) and c-Jun were also lower in liver tissue of LZ-Tg mice. Survival from severe oxidant injury induced by paraquat was twofold greater in LZ-Tg mice. In addition, LZ-Tg mice were resistant to chronic exogenous oxidant stress (OS) induced by AGE administration. Preincubation of hepatocytes (Hep G2) with LZ suppressed redox balance at baseline, as well as OS after added paraquat, AGE, or H2O2. LZ also ameliorated paraquat-enhanced cell apoptosis in a dose-dependent manner and suppressed AGE-induced p66(Shc) expression and c-Jun phosphorylation in Hep G2 cells. Thus LZ provides protection against acute and chronic oxidant injury by mechanisms involving suppression of ROS generation and of OS response genes.
Liu
Huixian
H
Department of Geriatrics, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
Zheng
Feng
F
Cao
Qi
Q
Ren
Bin
B
Zhu
Li
L
Striker
Gary
G
Vlassara
Helen
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002645:Chickens; D005260:Female; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D019803:Glutathione Disulfide / Q000097:blood / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D010269:Paraquat / Q000494:pharmacology; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides / Q000378:metabolism; D016019:Survival Analysis
D048868:Adaptor Proteins, Signal Transducing; D017127:Glycation End Products, Advanced; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013481:Superoxides; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D009113:Muramidase; D005978:Glutathione; D010269:Paraquat; D019803:Glutathione Disulfide