Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells

Autor: Tomomi E. Kimura, Mark Bond, Aparna Duggirala, Andrew C. Newby, Charles C.T. Hindmarch, Richard C. Hewer, Mei-Zhen Cui
Rok vydání: 2014
Předmět:
Male
rac1 GTP-Binding Protein
endocrine system
Adenosine
Vascular smooth muscle
Zif268
Myocytes
Smooth Muscle
Primary Cell Culture
Phosphodiesterase 3
3'-5'-Cyclic adenosine monophosphate
Aminopyridines
Early growth response gene 1
Exchange protein activated by cAMP
Biology
CREB
Muscle
Smooth
Vascular
Rats
Sprague-Dawley
chemistry.chemical_compound
Serum response factor
Cyclic AMP
Human Umbilical Vein Endothelial Cells
Cyclic AMP Response Element-Binding Protein
Animals
Guanine Nucleotide Exchange Factors
Protein kinase A
Molecular Biology
Cell Proliferation
Early Growth Response Protein 1
ets-Domain Protein Elk-1
Forskolin
Colforsin
Cyclic AMP-Dependent Protein Kinases
Epoprostenol
Molecular biology
Rats
Cell biology
3′-5′-Cyclic adenosine monophosphate
Gene Expression Regulation
chemistry
Organ Specificity
cardiovascular system
biology.protein
Original Article
Signal transduction
Cardiology and Cardiovascular Medicine
Protein Binding
Signal Transduction
Zdroj: Journal of Molecular and Cellular Cardiology
ISSN: 0022-2828
DOI: 10.1016/j.yjmcc.2014.02.001
Popis: Aims Cyclic AMP inhibits vascular smooth muscle cell (VSMC) proliferation which is important in the aetiology of numerous vascular diseases. The anti-mitogenic properties of cAMP in VSMC are dependent on activation of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), but the mechanisms are unclear. Methods and results Selective agonists of PKA and EPAC synergistically inhibited Egr1 expression, which was essential for VSMC proliferation. Forskolin, adenosine, A2B receptor agonist BAY60-6583 and Cicaprost also inhibited Egr1 expression in VSMC but not in endothelial cells. Inhibition of Egr1 by cAMP was independent of cAMP response element binding protein (CREB) activity but dependent on inhibition of serum response element (SRE) activity. SRF binding to the Egr1 promoter was not modulated by cAMP stimulation. However, Egr1 expression was dependent on the SRF co-factors Elk1 and 4 but independent of MAL. Inhibition of SRE-dependent Egr1 expression was due to synergistic inhibition of Rac1 activity by PKA and EPAC, resulting in rapid cytoskeleton remodelling and nuclear export of ERK1/2. This was associated with de-phosphorylation of the SRF co-factor Elk1. Conclusion cAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. This occurs, at least in part, via inhibition of Rac1 activity leading to rapid actin-cytoskeleton remodelling, nuclear export of ERK1/2, impaired Elk1-phosphorylation and inhibition of SRE activity. This identifies one of the earliest mechanisms underlying the anti-mitogenic effects of cAMP in VSMC but not in endothelial cells, making it an attractive target for selective inhibition of VSMC proliferation.
Highlights • cAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. • PKA and Epac synergise to inhibit Egr1 expression. • cAMP-mediated inhibition of Egr1 is cell-type specific. • cAMP inhibits SRE-dependent Egr1 transcription. • cAMP inhibits Egr1 via nuclear export of ERK1/2 and de-phosphorylation of Elk1.
Databáze: OpenAIRE
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