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Deprecated: Implicit conversion from float 213.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Br+J+Pharmacol 2012 ; 167 (7): 1492-505 Nephropedia Template TP
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Hydrogen sulfide inhibits the translational expression of hypoxia-inducible factor-1alpha #MMPMID22831549
Wu B; Teng H; Yang G; Wu L; Wang R
Br J Pharmacol 2012[Dec]; 167 (7): 1492-505 PMID22831549show ga
BACKGROUND AND PURPOSE: The accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) is under the influence of hydrogen sulfide (H(2) S), which regulates hypoxia responses. The regulation of HIF-1alpha accumulation by H(2) S has been shown, but the mechanisms for this effect are largely elusive and controversial. This study aimed at addressing the controversial mechanisms for and the functional importance of the interaction of H(2) S and HIF-1alpha protein. EXPERIMENTAL APPROACH: HIF-1alpha protein levels and HIF-1alpha transcriptional activity were detected by Western blotting and luciferase assay. The mechanisms for H(2) S-regulated HIF-1alpha protein levels were determined using short interfering RNA transfection, co-immunoprecipitation and 7-methyl-GTP sepharose 4B pull-down assay. Angiogenic activity was evaluated using tube formation assay in EA.hy926 cells. KEY RESULTS: The accumulation of HIF-1alpha protein under hypoxia (1% O(2) ) or hypoxia-mimetic conditions was reversed by sodium hydrosulfide (NaHS). This effect of NaHS was not altered after blocking the ubiquitin-proteasomal pathway for HIF-1alpha degradation; however, blockade of protein translation with cycloheximide abolished the effect of NaHS on the half-life of HIF-1alpha protein. Knockdown of eukaryotic translation initiation factor 2alpha (eIF2alpha) suppressed the effect of NaHS on HIF-1alpha protein accumulation under hypoxia. NaHS inhibited the expression of VEGF under hypoxia. It also decreased in vitro capillary tube formation and cell proliferation of EA.hy926 cells under hypoxia, but stimulated the tube formation under normoxia. CONCLUSIONS AND IMPLICATIONS: H(2) S suppresses HIF-1alpha translation by enhancing eIF2alpha phosphorylation under hypoxia. The interaction of H(2) S and HIF-1alpha inhibits the angiogenic activity of vascular endothelial cells under hypoxia through the down-regulation of VEGF.