on February 12, 2004
Published online before print February 12, 2004, doi: 10.1161/01.ATV.0000121570.00515.dc
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Submitted on December 10, 2003
Accepted on January 2, 2004
Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB
Jordi Rius ;
From the Centro de Investigación Cardiovascular, CSIC/ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
* To whom correspondence should be addressed. E-mail: lbmucv{at}cid.csic.es.
Objective--Low density lipoproteins (LDLs) modulate the expression of key genes involved in atherogenesis. Recently, we have shown that the transcription factor neuron-derived orphan receptor-1 (NOR-1) is involved in vascular smooth muscle cell (VSMC) proliferation. Our aim was to analyze whether NOR-1 is involved in LDL-induced mitogenic effects in VSMC.
Methods and Results--LDL induced NOR-1 expression in a time- and dose-dependent manner. Antisense oligonucleotides against NOR-1 inhibit DNA synthesis induced by LDL in VSMCs as efficiently as antisense against the protooncogene c-fos. The upregulation of NOR-1 mRNA levels by LDL involves pertusis-sensitive G protein-coupled receptors, Ca2+ mobilization, protein kinases A (PKA) and C (PKC) activation, and mitogen-activated protein kinase pathways (MAPK) (p44/p42 and p38). LDL promotes cAMP response element binding protein (CREB) activation (phosphorylation in Ser133), and in transfection assays a dominant-negative of CREB that inhibits NOR-1 promoter activity, while mutation of specific (cAMP response element) CRE sites in the NOR-1 promoter abolishes LDL-induced NOR-1 promoter activity.
Conclusions--In VSMCs, LDL-induced mitogenesis involves NOR-1 upregulation through a CREB-dependent mechanism. CREB could play a role in the modulation by LDL of key genes (containing CRE sites) involved in atherogenesis.
Key words: atherosclerosis • lipoproteins • smooth muscle cells • gene expression • proliferation
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