title: NCX1 is a novel target gene for hypoxia-inducible factor-1 in ischemic brain preconditioning.
abstract: OBJECTIVE
  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.affiliation: Division of Pharmacology, Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Via S. Pansini 5, 80131 Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Valsecchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pignataro
authors.forename: Annalisa
authors.initials: A
authors.lastname: Del Prete
authors.forename: Rossana
authors.initials: R
authors.lastname: Sirabella
authors.forename: Carmela
authors.initials: C
authors.lastname: Matrone
authors.forename: Francesca
authors.initials: F
authors.lastname: Boscia
authors.forename: Antonella
authors.initials: A
authors.lastname: Scorziello
authors.forename: Maria Josè
authors.initials: MJ
authors.lastname: Sisalli
authors.forename: Elga
authors.initials: E
authors.lastname: Esposito
authors.forename: Nicola
authors.initials: N
authors.lastname: Zambrano
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1