title: Distinct effects of Nampt inhibition on mild and severe models of lipopolysaccharide-induced myocardial impairment.
abstract: The study aimed to investigate the variance of myocardial and serum Nampt levels and the role of Nampt inhibition by FK866 in relatively mild endotoxemia- and severe endotoxemia-induced myocardial injury. Different doses of LPS were injected intraperitoneally to establish relatively mild endotoxemia (4mg/kg) and severe endotoxemia (20mg/kg). FK866 (10mg/kg b.w.) was injected intraperitoneally at hour one after LPS injection. The hearts were isolated from rats at hour six after LPS treatment and mounted in a Langendorff setup to measure cardiac function. Myocardial expression of Nampt was determined with immunohistochemistry assay and western blot. Serum Nampt level and myocardial TNF-α level were determined with ELISA. The myocardial level of TNF-α mRNA was detected with RT-PCR. The degree of myocardial oxidative injury was reflected by measuring lipid peroxidation and GSH/GSSG ratio. The apoptosis of cardiomyocytes was determined with detecting caspase-3 activity and with TUNEL assay. Myocardial expression of Nampt was markedly increased in 4mg/kg LPS-induced endotoxemia but decreased in 20mg/kg LPS-induced endotoxemia. Serum Nampt level was consistently up-regulated in both severities of endotoxemia. Inhibition of Nampt by FK866 reduced myocardial inflammation, oxidative injury and apoptosis of cardiomyocytes and improved cardiac function in 4mg/kg LPS-induced endotoxemia. In 20mg/kg LPS-induced endotoxemia, FK866 reduced myocardial inflammation, exacerbated apoptosis of cardiomyocytes, and failed to attenuate myocardial oxidative injury and cardiac dysfunction. In conclusion, the variance of myocardial Nampt expression may be associated with severities of endotoxemia. Nampt may play complicated roles and consequently application of Nampt inhibition should be critically evaluated in endotoxemia-induced myocardial impairment.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Canxin
authors.initials: C
authors.lastname: Liang
authors.forename: Dongwei
authors.initials: D
authors.lastname: He
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Xinwei
authors.initials: X
authors.lastname: Liu
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000276:immunology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000178:Acrylamides; D008070:Lipopolysaccharides; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; D054409:Nicotinamide Phosphoribosyltransferase; D053148:Caspase 3
keywords: Apoptosis; Endotoxemia; Inflammation; Myocardium; Nicotinamide phosphoribosyltransferase; Oxidative injury