title: Chronic hypoxia modulates the interleukin-1beta-stimulated inducible nitric oxide synthase pathway in cardiac myocytes.
abstract: BACKGROUND
  We wished to determine whether the cytokine-inducible nitric oxide synthase (iNOS) pathway is modulated by chronic hypoxia in vitro.
  
  
  RESULTS
  We investigated the effects of the proinflammatory cytokine interleukin (IL)-1beta on expression of iNOS mRNA, iNOS protein, and NO production in cultured neonatal rat cardiomyocytes subjected to 1% O2 for 48 hours. Among several cytokines tested, IL-1beta was the most effective in stimulating NO production, which was maximum at 48 hours. In parallel, IL-1beta induced expression of both iNOS mRNA and protein. Hypoxia alone had no effect on NO production, iNOS gene expression, or protein induction. However, chronic hypoxia decreased IL-1beta-stimulated NO production, mRNA expression, and protein level in cardiac myocytes. Radioligand binding and electrophoretic mobility shift assays showed that during chronic hypoxia, IL-1 receptor density and activity of the transcription factor NF-kappaB induced by IL-1beta were decreased, which may account at least in part for the decrease in iNOS expression.
  
  
  CONCLUSIONS
  These data indicate that IL-1beta induces iNOS gene expression, de novo synthesis of iNOS protein, and NO generation in neonatal rat cardiomyocytes and that chronic hypoxia appears to be a potent negative regulator of iNOS expression in these cells.
authors.affiliation: Veterans Affairs Medical Center, the Cardiovascular Research Institute, and the Department of Medicine, University of California, San Francisco 94121, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kacimi
authors.forename: C S
authors.initials: CS
authors.lastname: Long
authors.forename: J S
authors.initials: JS
authors.lastname: Karliner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002908:Chronic Disease; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D019833:Genistein; D000860:Hypoxia / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009206:Myocardium / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007529:Isoflavones; D016328:NF-kappa B; D009281:Naphthalenes; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003907:Dexamethasone; D019833:Genistein; D019001:Nitric Oxide Synthase; C058819:calphostin C