title: NO donor KMUP-1 improves hepatic ischemia-reperfusion and hypoxic cell injury by inhibiting oxidative stress and pro-inflammatory signaling.
abstract: This study investigates whether KMUP-1 improves hepatic ischemia-reperfusion (I/R) and hypoxic cell injury via inhibiting Nox2- and reactive oxygen species (ROS)-mediated pro-inflammation. Rats underwent ischemia by occlusion of the portal vein and hepatic artery for 45 minutes. Reperfusion was allowed for 4 h. Serum was used for analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). DNA extracted from liver homogenate was analyzed by electrophoresis to observe the fragmentation. Lipid peroxidation (LPO) was evaluated by measuring thiobarbituric acid-reactive substances (TBARS). NO and ROS contents were measured using Griess reagent and 2′-7′-dichlorofluorescein, respectively. Proteins levels were visualized by Western blotting. Liver damage was observed under a microscope. Intravenous KMUP-1 (0.25, 0.5 and 1 mg/kg) reduced I/R-induced ALT and AST levels, DNA fragmentation, ROS and malondialdehyde (MDA) and restored the NO levels of I/R rats. KMUP-1 protected the liver architecture from worsening of damage and focal sinusoid congestion, increased endothelium NO synthase (eNOS), guanosine 3', 5'cyclic monophosphate (cGMP), protein kinase G (PKG) and the B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio, attenuated phosphodiesterase 5A (PDE-5A) and cleaved caspase-3 expression in I/R-liver. In hypoxic HepG2 cells, KMUP-1 increased cGMP/PKG, restored peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and decreased matrix metalloproteinases-9 (MMP-9), Rho kinase II (ROCK II), hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelium growth factor (VEGF). KMUP-1 protects liver from I/R-injury and hypoxic hepatocytes from apoptosis-associated free radical generation and pro-inflammation by restoring/increasing NO/cGMP/PPAR-gamma, reducing ROS/Nox2 and inhibiting ROCKII/MMP-9.
authors.affiliation: Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: K K
authors.initials: KK
authors.lastname: Kuo
authors.forename: B N
authors.initials: BN
authors.lastname: Wu
authors.forename: E Y
authors.initials: EY
authors.lastname: Chiu
authors.forename: C J
authors.initials: CJ
authors.lastname: Tseng
authors.forename: J L
authors.initials: JL
authors.lastname: Yeh
authors.forename: C P
authors.initials: CP
authors.lastname: Liu
authors.forename: C Y
authors.initials: CY
authors.lastname: Chai
authors.forename: I J
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D053938:DNA Fragmentation; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D008562:Membrane Glycoproteins; D020030:Nitric Oxide Donors; D047495:PPAR gamma; D010880:Piperidines; D020011:Protective Agents; D017382:Reactive Oxygen Species; D014970:Xanthines; C439304:KMUP 1; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D017869:Cyclic GMP-Dependent Protein Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9