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.
Highlights
Vascular remodelling enables the healing and adaptation of blood vessels to mechanical injury or hemodynamic changes, and underlies pathogenic processes such as atherosclerosis, restenosis and abdominal aortic aneurysm (AAA)[1,2]
The expression of neuron-derived orphan receptor 1 (NOR-1) and cIAP2 is increased in AAA tissues
We analyzed the expression of NOR-1 and cIAP2 in human AAA tissues, samples in which vascular cells are exposed to conditions that compromise their survival, and in aortas from healthy donors
Summary
Vascular remodelling enables the healing and adaptation of blood vessels to mechanical injury or hemodynamic changes, and underlies pathogenic processes such as atherosclerosis, restenosis and abdominal aortic aneurysm (AAA)[1,2]. The members of the inhibitor of apoptosis (IAP) family are critical proteins regulating apoptosis[5]. IAPs are structurally related proteins that promote pro-survival signalling pathways and prevent the activation of the effector phase of apoptosis by interfering caspase activity. CIAP2 ( known as HIAP1 or BIRC3) is a potent inhibitor of apoptotic death that, in contrast to other members of the IAP family, is transcriptionally inducible by a number of triggers in different cell types including vascular cells[9,10,11], and is up-regulated in human tissues such as atherosclerotic plaques[12,13]. In the present study we show that cIAP2 is a direct target of NOR-1, and analyze the role of this anti-apoptotic protein in the pro-survival effects of NOR-1 in response to hypoxic stress
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