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Molecular and Cellular Biology, November 2009, p. 5828-5842, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00945-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Hypoxia-Inducible Factor 1/NOR-1 Axis Regulates the Survival Response of Endothelial Cells to Hypoxia{triangledown}

Lluis Martorell,{dagger} Maurizio Gentile,{dagger} Jordi Rius,{ddagger} Cristina Rodríguez, Javier Crespo, Lina Badimon, and José Martínez-González*

Cardiovascular Research Center (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Received 18 July 2009/ Accepted 21 August 2009

Hypoxia induces apoptosis but also triggers adaptive mechanisms to ensure cell survival. Here we show that the prosurvival effects of hypoxia-inducible factor 1 (HIF-1) in endothelial cells are mediated by neuron-derived orphan receptor 1 (NOR-1). The overexpression of NOR-1 decreased the rate of endothelial cells undergoing apoptosis in cultures exposed to hypoxia, while the inhibition of NOR-1 increased cell apoptosis. Hypoxia upregulated NOR-1 mRNA levels in a time- and dose-dependent manner. Blocking antibodies against VEGF or SU5614 (a VEGF receptor 2 inhibitor) did not prevent hypoxia-induced NOR-1 expression, suggesting that NOR-1 is not induced by the autocrine secretion of VEGF in response to hypoxia. The reduction of HIF-1{alpha} protein levels by small interfering RNAs, or by inhibitors of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 upregulation. Intracellular Ca2+ was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 upregulation. A hypoxia response element mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, the attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 overexpression upregulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cells to hypoxia.

* Corresponding author. Mailing address: Cardiovascular Research Center (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau (Pabellón N° 11), c/Sant Antoni Maria Claret #167, 08025 Barcelona, Spain. Phone: (34) 935565896. Fax: (34) 935565559. E-mail: jmartinez{at}csic-iccc.org

{triangledown} Published ahead of print on 31 August 2009.

{dagger} Both authors contributed equally.

{ddagger} Present address: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, CA 92093.

Molecular and Cellular Biology, November 2009, p. 5828-5842, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00945-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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