RGD Reference Report - cAMP inhibits transforming growth factor-beta-stimulated collagen synthesis via inhibition of extracellular signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts. - Rat Genome Database

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cAMP inhibits transforming growth factor-beta-stimulated collagen synthesis via inhibition of extracellular signal-regulated kinase 1/2 and Smad signaling in cardiac fibroblasts.

Authors: Liu, X  Sun, SQ  Hassid, A  Ostrom, RS 
Citation: Liu X, etal., Mol Pharmacol. 2006 Dec;70(6):1992-2003. Epub 2006 Sep 7.
RGD ID: 1599906
Pubmed: PMID:16959941   (View Abstract at PubMed)
DOI: DOI:10.1124/mol.106.028951   (Journal Full-text)

Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Cytokines such as transforming growth factor-beta (TGF-beta) play a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and other profibrotic responses, but less is known about pathways that might inhibit fibrosis. Increased cAMP formation inhibits myofibroblast differentiation and collagen production by cardiac fibroblasts, but the mechanism of this inhibition is not known. We sought to characterize the signaling pathways by which cAMP-elevating agents alter collagen expression and myofibroblast differentiation. Treatment with 10 microM forskolin or isoproterenol increased cAMP production and cAMP response element binding protein (CREB) phosphorylation in cardiac fibroblasts and inhibited serum- or TGF-beta-stimulated collagen synthesis by 37% or more. These same cAMP-elevating agents blunted TGF-beta-stimulated expression of collagen I, collagen III, and alpha-smooth muscle actin. Forskolin or isoproterenol treatment blocked the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by TGF-beta despite the fact that these cAMP-elevating agents stimulated ERK1/2 activation on their own. cAMP-elevating agents also attenuated the activation of c-Jun NH(2)-terminal kinase and reduced binding of the transcriptional coactivator CREB-binding protein 1 to transcriptional complexes containing Smad2, Smad3, and Smad4. Pharmacological inhibition of ERK completely blocked TGF-beta-stimulated collagen gene expression, but expression of an active mutant of MEK was additive with TGF-beta treatment. Thus, cAMP-elevating agents inhibit the profibrotic effects of TGF-beta in cardiac fibroblasts largely through inhibiting ERK1/2 phosphorylation but also by reducing Smad-mediated recruitment of transcriptional coactivators.

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein-containing complex  IDA 1599906; 1599906 RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

Objects Annotated

Genes (Rattus norvegicus)
Creb1  (cAMP responsive element binding protein 1)
Crebbp  (CREB binding protein)
Smad2  (SMAD family member 2)
Smad4  (SMAD family member 4)

Genes (Mus musculus)
Smad2  (SMAD family member 2)
Smad4  (SMAD family member 4)

Genes (Homo sapiens)
SMAD2  (SMAD family member 2)
SMAD4  (SMAD family member 4)

Objects referenced in this article
Gene SMAD3 SMAD family member 3 Homo sapiens
Gene Smad3 SMAD family member 3 Mus musculus
Gene Smad3 SMAD family member 3 Rattus norvegicus

Additional Information