The HIF-1/NOR-1 Axis Regulates the Survival Response of Endothelial Cells to Hypoxia.
2009, Mol Cell Biol. 2009 Aug 31. [Epub ahead of print]
Martorell L, Gentile M, Rius J, Rodríguez C, Crespo J, Badimon L, Martínez-González J.
Autors del centre relacionats: Badimon Lina, Crespo Javier, Martínez-González Jose, Rodríguez Cristina.
Martorell L, Gentile M, Rius J, Rodríguez C, Crespo J, Badimon L, Martínez-González J.
Autors del centre relacionats: Badimon Lina, Crespo Javier, Martínez-González Jose, Rodríguez Cristina.
Cardiovascular Research Center (CSIC-ICCC), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, California 92093.
Hypoxia induces apoptosis but also triggers adaptive mechanisms to insure cell survival. Here we show that the pro-survival effects of hypoxia-inducible factor-1 (HIF-1) in endothelial cells are mediated by NOR-1. The over-expression 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 up-regulated 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. Reduction of HIF-1alpha protein levels by siRNAs, or by inhibitors of phosphatidylinositol-3 kinase/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 up-regulation. Intracellular Ca(2+) was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 up-regulation. A hypoxia response element (HRE) mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 over-expression up-regulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cell to hypoxia.
PMID: 19720740 [PubMed - as supplied by publisher]
Hypoxia induces apoptosis but also triggers adaptive mechanisms to insure cell survival. Here we show that the pro-survival effects of hypoxia-inducible factor-1 (HIF-1) in endothelial cells are mediated by NOR-1. The over-expression 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 up-regulated 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. Reduction of HIF-1alpha protein levels by siRNAs, or by inhibitors of phosphatidylinositol-3 kinase/Akt pathway or mTOR, significantly counteracted hypoxia-induced NOR-1 up-regulation. Intracellular Ca(2+) was involved in hypoxia-induced PI3K/Akt activation and in the downstream NOR-1 up-regulation. A hypoxia response element (HRE) mediated the transcriptional activation of NOR-1 induced by hypoxia as we show by transient transfection and chromatin immunoprecipitation assays. Finally, attenuation of NOR-1 expression reduced both basal and hypoxia-induced cIAP2 (cellular inhibitor of apoptosis protein 2) mRNA levels, while NOR-1 over-expression up-regulated cIAP2. Therefore, NOR-1 is a downstream effector of HIF-1 signaling involved in the survival response of endothelial cell to hypoxia.
PMID: 19720740 [PubMed - as supplied by publisher]
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