The Intima

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Members of the nuclear hormone receptor superfamily function as key transcriptional regulators of inflammation and proliferation in cardiovascular diseases. In addition to the ligand-dependent peroxisome proliferator-activated receptors and liver X receptors, this family of transcription factors includes a large number of orphan receptors, and their role in vascular diseases remains to be investigated. The neuron-derived orphan receptor-1 (NOR1) belongs to the ligand-independent NR4A subfamily, which has been implicated in cell proliferation, differentiation, and apoptosis. In this study, we demonstrate NOR1 expression in vascular smooth muscle cells (SMC) of human atherosclerotic lesions. In response to mitogenic stimulation with platelet-derived growth factor (PDGF), SMC rapidly express NOR1 through an ERK-MAPK-dependent signaling pathway. 5-Deletion analysis, site-directed mutagenesis, and transactivation experiments demonstrate that PDGF-induced NOR1 expression is mediated through a cAMPresponse element-binding protein (CREB)-dependent transactivation of the NOR1 promoter. Consequently, short interfering RNAmediated depletion of CREB abolished PDGF-induced NOR1 expression in SMC. Furthermore, PDGF induced Ser-133 phosphorylation of CREB and subsequent binding to the CRE sites of the endogenous NOR1 promoter. Functional analysis demonstrated that PDGF induces NOR1 transactivation of its consensus NGFI-B-response elements (NBRE) in SMC. We finally demonstrate that SMC isolated from NOR1-deficient mice exhibit decreased cell proliferation and characterize cyclin D1 and D2 as NOR1 target genes in SMC. These experiments indicate that PDGF-induced NOR1 transcription in SMC is mediated through CREB-dependent transactivation of the NOR1 promoter and further demonstrate that NOR1 functions as a key transcriptional regulator of SMC proliferation.Atherosclerosis, the subsequent development of occlusive vascular diseases, and the failure of treatment approaches such as postangioplasty restenosis involve several interrelated processes (1, 2). In addition to endothelial dysfunction and inflammation, proliferation of smooth muscle cells (SMC) 3 is considered to play a pivotal role in the pathogenesis of atherosclerosis and the failure of interventional approaches used to treat related occlusive vascular complications (2-4). With the evolving understanding of the mechanisms contributing to the development of vascular diseases, members of the nuclear hormone receptor superfamily of transcription factors have emerged as key transcriptional regulators of inflammation and cell proliferation (5, 6). Based on this evidence, elucidation of the molecular pathways utilized by nuclear receptors to regulate programs of gene expression is expected to facilitate the development of novel pharmacological approaches for the treatment of cardiovascular diseases. Nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies are expressed in SMC and inhibit their proliferation in response ...

Section: Discussionmentioning

confidence: 67%

Section: Nor1 Is Expressed In Human Atheroscleroticmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation

Nomiyama

Nakamachi

Gizard

et al. 2006

117

150

“…2 migration and proliferation contribute to the pathogenesis of atherosclerosis and restenosis (1)(2)(3). It has been shown that 15-lipoxygenase 1 (15-Lox1) and its murine ortholog 12/15-Lox mediate the oxidation of low density lipoprotein, an important factor in the disease process of atherosclerosis (4,5).…”

Section: Vascular Smooth Muscle Cell (Vsmc)mentioning

confidence: 99%

15-Lipoxygenase-1-enhanced Src-Janus Kinase 2-Signal Transducer and Activator of Transcription 3 Stimulation and Monocyte Chemoattractant Protein-1 Expression Require Redox-sensitive Activation of Epidermal Growth Factor Receptor in Vascular Wall Remodeling

Singh

Wang

Kundumani‐Sridharan

et al. 2011

To understand the mechanisms by which 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) activates signal transducer and activator of transcription 3 (STAT3), we studied the role of epidermal growth factor receptor (EGFR). 15(S)-HETEwhereas dominant negative Src blocked BI-induced 15-Lox1-enhanced Jak2 phosphorylation, dnJak2 had no effect on Src phosphorylation. Together, these observations demonstrate for the first time that the 15-Lox1-15(S)-HETE axis activates EGFR via redox-sensitive manner, which in turn mediates Src-Jak2-STAT3-dependent MCP-1 expression leading to vascular wall remodeling.

“…3 migration from media to intima plays a determinant role in atherosclerosis and restenosis (1)(2)(3). Arachidonic acid (AA) and its oxygenated metabolites, collectively known as eicosanoids, are involved in the maintenance of vascular tone (4,5).…”

Section: Vsmcmentioning

confidence: 99%

Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration

Potula

Wang

Quyền

et al. 2009

VSMC3 migration from media to intima plays a determinant role in atherosclerosis and restenosis (1-3). Arachidonic acid (AA) and its oxygenated metabolites, collectively known as eicosanoids, are involved in the maintenance of vascular tone (4, 5). Lipoxygenases (LOXs) are non-heme iron dioxygenases that stereospecifically introduce molecular oxygen into polyunsaturated fatty acids, resulting in the formation of hydroperoxyeicosatetraenoic acids, which are subsequently converted to hydroxyeicosatetraenoic acids (HETEs) (6). Two 15-LOXs, namely, 15-LOX1 and 15-LOX2, have been shown to be expressed in humans (7,8). Both enzymes metabolize linoleic acid to 13(S)-hydroperoxyoctadecadienoic acid and AA to 15(S)-hydroperoxyeicosatetraenoic acid preferentially (9, 10). In regard to their tissue distribution, whereas 15-LOX1 shows a narrow cell-specific expression, including human reticulocytes and airway epithelial cells, 15-LOX2 appears to be expressed in epithelial cell types in cornea, lung, prostate, and skin (11). The studies from our laboratory showed that both 15-LOX1 and 15-LOX2 are expressed in human retinal microvascular endothelial cells (12). Although the presence of 15-LOX2 in VSMC has yet to be reported, these cells express 15-LOX1 (also known as 12/15-LOX in murines) and, when exposed to AA, produce both 15(S)-HETE and 12(S)-HETE (13,14). It is also known that 15-LOX1 and 12/15-LOX are involved in the oxidation of low density lipoprotein, a contributing factor in the pathogenesis of atherosclerosis (15, 16). Furthermore, using either transgenic or knock-out mice models, a number of studies have demonstrated that 15-LOX1 and its murine ortholog 12/15-LOX play a role in atherosclerosis and restenosis (17)(18)(19). In addition, human atheroma homogenates upon incubation with AA converted it mainly to .In recent years LOX products of polyunsaturated fatty acids have also been shown to be potent chemoattractants for resi-* This work was supported, in whole or in part, by National Institutes of Health Grant HL064165 (NHLBI; to G. N. R.