ArticleJournal of molecular and cellular cardiology2014
Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells.
Article in Journal of molecular and cellular cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- The Salmonella pathogenicity island 1 injectisome reprograms host cell translation to evade the inflammatory response.Nature communications · 2025Article
- Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.Pharmacological reviews · 2025Review
- Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes.Circulation research · 2023Article
- Article
- The Role of Epac in Cancer Progression.International journal of molecular sciences · 2020Review
- EPAC in Vascular Smooth Muscle Cells.International journal of molecular sciences · 2020Review
- Nuclear actin regulates cell proliferation and migration via inhibition of SRF and TEAD.Biochimica et biophysica acta. Molecular cell research · 2020Article
- Review
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- Dual Role of CREB in The Regulation of VSMC Proliferation: Mode of Activation Determines Pro- or Anti-Mitogenic Function.Scientific reports · 2018Article
- The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury.EBioMedicine · 2017Article
- Gene expression profiles and signaling mechanisms in αBMC systems biology · 2017Article
- Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors.Scientific reports · 2017Article
- Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac.British journal of pharmacology · 2017Article
- The Hippo pathway mediates inhibition of vascular smooth muscle cell proliferation by cAMP.Journal of molecular and cellular cardiology · 2016Article
- MicroRNA Regulatory Network Revealing the Mechanism of Inflammation in Atrial Fibrillation.Medical science monitor : international medical journal of experimental and clinical research · 2015Article
- The future of EPAC-targeted therapies: agonism versus antagonism.Trends in pharmacological sciences · 2015Review
- cAMP-induced actin cytoskeleton remodelling inhibits MKL1-dependent expression of the chemotactic and pro-proliferative factor, CCN1.Journal of molecular and cellular cardiology · 2015Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
aimsCyclic 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
resultsSelective 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.
conclusioncAMP 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.