NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning.

Abstract

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-1α 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.

• Authors: Valeria Valsecchi, Giuseppe Pignataro, Annalisa Del Prete, Rossana Sirabella, Carmela Matrone, Francesca Boscia, Antonella Scorziello, Maria Josè Sisalli, Elga Esposito, Nicola Zambrano, Gianfranco Di Renzo, Lucio Annunziato
• Journal: Stroke (Stroke) Vol. 42 Issue 3 Pg. 754-63 (Mar 2011) ISSN: 1524-4628 [Electronic] United States
• PMID: 21293012 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Sodium-Calcium Exchanger
• sodium-calcium exchanger 1

Topics

• Animals
• Brain (blood supply, metabolism)
• Cell Line, Tumor
• Cells, Cultured
• Gene Targeting (methods)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, physiology)
• Ischemic Attack, Transient (genetics, metabolism)
• Ischemic Preconditioning (methods)
• Male
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Sodium-Calcium Exchanger (biosynthesis, genetics, metabolism)