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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Stroke 2011 ; 42 (3): 754-63 Nephropedia Template TP
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NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning #MMPMID21293012
Valsecchi V; Pignataro G; Del Prete A; Sirabella R; Matrone C; Boscia F; Scorziello A; Sisalli MJ; Esposito E; Zambrano N; Di Renzo G; Annunziato L
Stroke 2011[Mar]; 42 (3): 754-63 PMID21293012show ga
BACKGROUND AND PURPOSE: The sodium-calcium exchanger-1 (NCX1) represents a key mediator for maintaining [Na(+)](i) and [Ca(2+)](i) homeostasis. Although changes in NCX1 protein and transcript expression have been detected during stroke, its transcriptional regulation is still unknown. Thus far, however, there is evidence that hypoxia-inducible factor-1 (HIF-1) is a nuclear factor required for transcriptional activation of several genes implicated in stroke. The main objective of this study was to investigate whether NCX1 gene might be a novel target of HIF-1 in the brain. METHODS: Here we report that: (1) in neuronal cells, NCX1 increased expression after oxygen and glucose deprivation or cobalt-induced HIF-1 activation was prevented by silencing HIF-1; (2) the brain NCX1 promoter cloned upstream of the firefly-luciferase gene contained 2 regions of HIF-1 target genes called hypoxia-responsive elements that are sensitive to oxygen and glucose deprivation or cobalt chloride; (3) HIF-1 specifically bound hypoxia-responsive elements on brain NCX1, as demonstrated by band-shift and chromatin immunoprecipitation assays; (4) HIF-1alpha silencing prevented NCX1 upregulation and neuroprotection induced by ischemic preconditioning; and (5) NCX1 silencing partially reverted the preconditioning-induced neuroprotection in rats. CONCLUSIONS: NCX1 gene is a novel HIF-1 target, and HIF-1 exerts its prosurvival role through NCX1 upregulation during brain preconditioning.