title: Myoglobin induces vascular cell adhesion molecule-1 expression through c-Src kinase-activator protein-1/nuclear factor-kappaB pathways.
abstract: OBJECTIVE
  It is not clear whether a sublethal dose of myoglobin induces some pathophysiological changes in tubular cells, potentially affecting tubular injury or tubular regeneration. We investigated the effect of a low dose of myoglobin on vascular cell adhesion molecule-1 (VCAM-1) expression and elucidated the underlying signaling pathways. We further examined the effect of losartan and simvastatin on myoglobin-induced VCAM-1 expression and the signaling pathways.
  
  
  METHODS
  Activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 was assessed by electrophoretic mobility shift assay. Phosphorylation of protein kinases was examined by Western blot analysis. VCAM-1 mRNA and protein were measured by Northern blot analysis and cell ELISA.
  
  
  RESULTS
  A sublethal dose of myoglobin (100 microg/ml) induced VCAM-1 expression via activation of AP-1 and NF-kappaB, which was mediated through activation of c-Src kinase, followed by mitogen-activated protein kinases (p38, ERK 1/2, JNK-1) and the I kappaB kinase - I kappaB-alpha. Inhibitors of protein kinase C and tyrosine kinase, antioxidants and intracellular calcium chelator suppressed myoglobin-induced activation of c-Src kinase. Losartan and simvastatin suppressed myoglobin-induced VCAM-1 expression via inhibition of c-Src kinase.
  
  
  CONCLUSIONS
  VCAM-1 expression via c-Src kinase-AP-1/NF-kappaB pathways might be one of the possible mechanisms linking myoglobin to tubular injury. Losartan and simvastatin might be beneficial in attenuating myoglobin-induced tubular injury.
authors.affiliation: Department of Internal Medicine, Asan Institute for Life Sciences, College of Medicine, University of Ulsan, Seoul, Korea.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Jai Won
authors.initials: JW
authors.lastname: Chang
authors.forename: Soon Bae
authors.initials: SB
authors.lastname: Kim
authors.forename: Su Kil
authors.initials: SK
authors.lastname: Park
authors.forename: Jung Sik
authors.initials: JS
authors.lastname: Park
authors.forename: Sang Koo
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009211:Myoglobin / Q000494:pharmacology / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*; D019061:src-Family Kinases
chemical_list: D000975:Antioxidants; D009211:Myoglobin; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; D019821:Simvastatin; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D019808:Losartan; D002118:Calcium