title: Tumor necrosis factor-alpha confers resistance to hypoxic injury in the adult mammalian cardiac myocyte.
abstract: BACKGROUND
  Previous studies in isolated cardiac myocytes have shown that tumor necrosis factor (TNF)-alpha provokes increased expression of 27- and 70-kD stress proteins as well as manganese superoxide dismutase, suggesting that TNF-alpha might play a role in mediating stress responses in the heart.
  
  
  RESULTS
  To determine whether TNF-alpha stimulation would protect isolated cardiac myocytes against environmental stress, myocyte cultures were pretreated with TNF-alpha for 12 hours and then subjected to continuous hypoxic injury (O2 content, 3 to 5 ppm) for 12 hours, followed by reoxygenation. Cell injury was assessed in terms of lactic dehydrogenase (LDH) release, 45Ca2+ uptake, and MTT metabolism. Pretreatment with TNF-alpha concentrations > or = 50 U/mL significantly attenuated LDH release by hypoxic cells compared with diluent-treated hypoxic cells. Similar findings were observed with respect to 45Ca2+ uptake and MTT metabolism in TNF-alpha-pretreated cells that were subjected to prolonged hypoxia. To determine the mechanism for the TNF-alpha-induced protective effect, the cells were pretreated with heat shock protein (HSP) 72 antisense oligonucleotides. These studies showed that the protective effect of TNF-alpha was not inhibited by antisense oligonucleotides, despite use of a concentration of antisense that was sufficient to attenuate the TNF-alpha-induced increase in HSP 72 expression. Subsequent studies using mutated TNF ligands showed that activation of both types 1 and 2 TNF receptors was sufficient to confer a protective response in isolated cardiac myocytes through an as yet unknown pathway(s).
  
  
  CONCLUSIONS
  Taken together, the above observations demonstrate that TNF-alpha pretreatment confers resistance to hypoxic stress in the adult cardiac myocyte through a novel mechanism that appears to be different from but not necessarily exclusive of the protective response conferred by HSP 72 expression.
authors.affiliation: Department of Medicine, Veterans Administration Medical Center, Baylor College of Medicine, Houston, Tex 77030, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nakano
authors.forename: A A
authors.initials: AA
authors.lastname: Knowlton
authors.forename: Z
authors.initials: Z
authors.lastname: Dibbs
authors.forename: D L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D002415:Cats; D015687:Cell Hypoxia / Q000187:drug effects*; D016922:Cellular Senescence; D050884:HSP72 Heat-Shock Proteins; D006321:Heart / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D013268:Stimulation, Chemical; D013312:Stress, Physiological / Q000517:prevention & control*; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002132:Calcium Radioisotopes; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D002118:Calcium