Myoglobin induces vascular cell adhesion molecule-1 expression through c-Src kinase-activator protein-1/nuclear factor-kappaB pathways.
BACKGROUND/AIMS: 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. CONCLUSION: 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.[1]References
- Myoglobin induces vascular cell adhesion molecule-1 expression through c-Src kinase-activator protein-1/nuclear factor-kappaB pathways. Kim, S.H., Chang, J.W., Kim, S.B., Park, S.K., Park, J.S., Lee, S.K. Nephron Exp. Nephrol. (2010) [Pubmed]
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