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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:697.)
© 2004 American Heart Association, Inc.

Vascular Biology

Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB

Jordi Rius; José Martínez-González; Javier Crespo; Lina Badimon

From the Centro de Investigación Cardiovascular, CSIC/ICCC, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Correspondence to Prof Lina Badimon, Laboratorio de Investigación Cardiovascular, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret # 167, 08025 Barcelona (Spain). 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). In transfection assays a dominant-negative of CREB 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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