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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Binding Sites
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Calcium Signaling
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Cells, Cultured / drug effects
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Cyclic AMP Response Element-Binding Protein / chemistry
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / physiology*
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Cyclic AMP-Dependent Protein Kinases / metabolism
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DNA Replication / drug effects
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Enzyme Activation
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Humans
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Lipoproteins, LDL / pharmacology*
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MAP Kinase Signaling System
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Mitosis / drug effects*
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Muscle, Smooth, Vascular / cytology*
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / drug effects*
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / genetics
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Protein Kinase C / metabolism
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RNA, Messenger / biosynthesis
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Rats
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Receptors, G-Protein-Coupled / physiology
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Receptors, Steroid
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Receptors, Thyroid Hormone
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Regulatory Sequences, Nucleic Acid
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Thionucleotides / pharmacology
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Transfection
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Up-Regulation / drug effects
Substances
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Cyclic AMP Response Element-Binding Protein
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DNA-Binding Proteins
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Lipoproteins, LDL
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NR4A3 protein, human
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Nerve Tissue Proteins
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Nr4a3 protein, rat
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Oligodeoxyribonucleotides, Antisense
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RNA, Messenger
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Receptors, G-Protein-Coupled
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Receptors, Steroid
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Receptors, Thyroid Hormone
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Thionucleotides
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C