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Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Pharmacol+Exp+Ther 2012 ; 342 (2): 561-7 Nephropedia Template TP
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Copper is required for cobalt-induced transcriptional activity of hypoxia-inducible factor-1 #MMPMID22619252
Qiu L; Ding X; Zhang Z; Kang YJ
J Pharmacol Exp Ther 2012[Aug]; 342 (2): 561-7 PMID22619252show ga
Cobalt inhibits prolyl hydroxylases, leading to the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) and a concomitant increase in the transcriptional activity of HIF-1. Therefore, cobalt has been under development as a drug for activating HIF-1 under some disease conditions. However, it has been shown that ischemic conditions resulted in the loss of copper, and the activation of HIF-1 would not occur unless copper was supplemented. The present study was undertaken to test the hypothesis that copper is also required for the cobalt activation of HIF-1 transcriptional activity. Human umbilical vein endothelial cells subjected to treatment with cobalt chloride (CoCl(2)) at concentrations above 25 muM for 2 h resulted in an accumulation of HIF-1alpha, which was determined by Western blot analysis, and an increase in the expression of vascular endothelial growth factor (VEGF), which was determined by real-time reverse transcription-polymerase chain reaction analysis for mRNA levels and enzyme-linked immunosorbent assay analysis for protein levels. The copper chelator tetraethylenepentamine at 25 muM did not significantly affect the accumulation of HIF-1alpha but blocked increases in VEGF mRNA and protein levels, an effect that could be reversed by the addition of 25 muM copper sulfate (CuSO(4)). In addition, gene silencing of the copper chaperone for Cu,Zn-superoxide dismutase blocked VEGF expression with little effect on cobalt-induced HIF-1alpha accumulation. The present study thus demonstrates that copper was required for cobalt-activated transcriptional activity of HIF-1, although copper did not affect cobalt-induced accumulation of HIF-1alpha in the cells.
J+Pharmacol+Exp+Ther 2012 ; 342 (2): 561-7
