Involvement of neuron-derived orphan receptor-1 (NOR-1) in LDL-induced mitogenic stimulus in vascular smooth muscle cells: role of CREB

Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):697-702. doi: 10.1161/01.ATV.0000121570.00515.dc. Epub 2004 Feb 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Binding Sites
  • Calcium Signaling
  • Cells, Cultured / drug effects
  • Cyclic AMP Response Element-Binding Protein / chemistry
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA Replication / drug effects
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Enzyme Activation
  • Humans
  • Lipoproteins, LDL / pharmacology*
  • MAP Kinase Signaling System
  • Mitosis / drug effects*
  • Muscle, Smooth, Vascular / cytology*
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects*
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein Kinase C / metabolism
  • RNA, Messenger / biosynthesis
  • Rats
  • Receptors, G-Protein-Coupled / physiology
  • Receptors, Steroid
  • Receptors, Thyroid Hormone
  • Regulatory Sequences, Nucleic Acid
  • Thionucleotides / pharmacology
  • Transfection
  • Up-Regulation / drug effects

Substances

  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Lipoproteins, LDL
  • NR4A3 protein, human
  • Nerve Tissue Proteins
  • Nr4a3 protein, rat
  • Oligodeoxyribonucleotides, Antisense
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Receptors, Steroid
  • Receptors, Thyroid Hormone
  • Thionucleotides
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C