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 ...

Abstract-Activation of the peroxisome proliferator-activated receptor (PPAR) ␥, the molecular target for insulin sensitizing thiazolidinediones used in patients with type 2 diabetes, inhibits vascular smooth muscle cell (VSMC) proliferation and prevents atherosclerosis and neointima formation. Emerging evidence indicates that telomerase controls key cellular functions including replicative lifespan, differentiation, and cell proliferation. In the present study, we demonstrate that ligand-induced and constitutive PPAR␥ activation inhibits telomerase activity in VSMCs.Telomerase reverse transcriptase (TERT) confers the catalytic activity of telomerase, and PPAR␥ ligands inhibit TERT expression through a receptor-dependent suppression of the TERT promoter. 5Ј-deletion analysis, site-directed mutagenesis, and transactivation studies using overexpression of Ets-1 revealed that suppression of TERT transcription by PPAR␥ is mediated through negative cross-talk with Ets-1-dependent transactivation of the TERT promoter.Chromatin immunoprecipitation assays further demonstrated that PPAR␥ ligands inhibit Ets-1 binding to the TERT promoter, which is mediated at least in part through an inhibition of Ets-1 expression by PPAR␥ ligands. In VSMCs overexpressing TERT, the efficacy of PPAR␥ ligands to inhibit cell proliferation is lost, indicating that TERT constitutes an important molecular target for the antiproliferative effects of PPAR␥ ligands. Finally, we demonstrate that telomerase activation during the proliferative response after vascular injury is effectively inhibited by PPAR␥ ligands. These findings provide a previously unrecognized mechanism for the antiproliferative effects of PPAR␥ ligands and support the concept that PPAR␥ ligands may constitute a novel therapeutic approach for the treatment of proliferative cardiovascular diseases.(Circ Res. 2006;98:e50-e59.)Key Words: telomerase Ⅲ peroxisome proliferator-activated receptor Ⅲ vascular smooth muscle cell Ⅲ proliferation P eroxisome proliferator-activated receptor (PPAR) ␥ is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. 1 Synthetic ligands include thiazolidinedione (TZD) PPAR␥ ligands, like rosiglitazone (RSG) or pioglitazone (PIO), which are clinically used as insulin sensitizers in patients with type 2 diabetes. TZD PPAR␥ agonists not only improve insulin resistance in patients with type 2 diabetes but also exert a broad spectrum of pleiotropic vascular effects in vitro and in animal models. 2 PPAR␥ is expressed in macrophages, endothelial cells, and vascular smooth muscle cells (VSMCs) and regulates gene expression of key proteins involved in glucose/lipid metabolism, vascular inflammation, and proliferation. 3 TZD PPAR␥ ligands prevent the development of atherosclerosis and intimal hyperplasia after balloon injury in animal models. 4 -6 Early clinical studies further demonstrate that PPAR␥ ligands prevent the progression of intima/media thickening used as sensitive measurement of atherosclerosis 7,8 and the de...

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