title: NOR-1/NR4A3 regulates the cellular inhibitor of apoptosis 2 (cIAP2) in vascular cells: role in the survival response to hypoxic stress.
abstract: Vascular cell survival is compromised under pathological conditions such as abdominal aortic aneurysm (AAA). We have previously shown that the nuclear receptor NOR-1 is involved in the survival response of vascular cells to hypoxia. Here, we identify the anti-apoptotic protein cIAP2 as a downstream effector of NOR-1. NOR-1 and cIAP2 were up-regulated in human AAA samples, colocalizing in vascular smooth muscle cells (VSMC). While NOR-1 silencing reduced cIAP2 expression in vascular cells, lentiviral over-expression of this receptor increased cIAP2 mRNA and protein levels. The transcriptional regulation of the human cIAP2 promoter was analyzed in cells over-expressing NOR-1 by luciferase reporter assays, electrophoretic mobility shift analysis and chromatin immunoprecipitation, identifying a NGFI-B site (NBRE-358/-351) essential for NOR-1 responsiveness. NOR-1 and cIAP2 were up-regulated by hypoxia and by a hypoxia mimetic showing a similar time-dependent pattern. Deletion and site-directed mutagenesis studies show that NOR-1 mediates the hypoxia-induced cIAP2 expression. While NOR-1 over-expression up-regulated cIAP2 and limited VSMC apoptosis induced by hypoxic stress, cIAP2 silencing partially prevented this NOR-1 pro-survival effect. These results indicate that cIAP2 is a target of NOR-1, and suggest that this anti-apoptotic protein is involved in the survival response to hypoxic stress mediated by NOR-1 in vascular cells.
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau), c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Alonso
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau), c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.|Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, IIB-Sant Pau, c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Galán
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau), c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Martí-Pàmies
authors.affiliation: Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, IIB-Sant Pau, c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Romero
authors.affiliation: Laboratorio de Angiología, Biología Vascular e Inflamación y Servicio de Cirugía Vascular, IIB-Sant Pau, c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Camacho
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau), c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), Instituto de Investigación Biomédica Sant Pau (IIB-Sant Pau), c/Sant Antoni Maria Claret 167, 08025 Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González