Myoglobin induces vascular cell adhesion molecule-1 expression through c-Src kinase-activator protein-1/nuclear factor-kappaB pathways.
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.
Kim
Sang Hyun
SH
Department of Internal Medicine, Asan Institute for Life Sciences, College of Medicine, University of Ulsan, Seoul, Korea.
Chang
Jai Won
JW
Kim
Soon Bae
SB
Park
Su Kil
SK
Park
Jung Sik
JS
Lee
Sang Koo
SK
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
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