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Received for publication July 18, 2006.
Revised August 17, 2006.
Accepted for publication September 6, 2006.
-STIMULATED COLLAGEN SYNTHESIS VIA INHIBITION OF ERK1/2 AND SMAD SIGNALING IN RAT CARDIAC FIBROBLASTS
Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Cytokines such as transforming growth factor-beta (TGF-
) play a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and other pro-fibrotic 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 µM forskolin or isoproterenol increased cAMP production and CREB phosphorylation in cardiac fibroblasts and inhibited serum- or TGF--stimulated collagen synthesis by 37% or more. These same cAMP-elevating agents blunted TGF--stimulated expression of collagen I, collagen III and 
-smooth muscle actin. Forskolin or isoproterenol treatment blocked the activation of ERK1/2 induced by TGF- despite the fact that these cAMP-elevating agents stimulated ERK1/2 activation on their own. cAMP-elevating agents also attenuated the activation of JNK and reduced binding of the transcriptional co-activator CBP1 to transcriptional complexes containing Smad2, Smad3 and Smad4. Pharmacological inhibition of ERK completely blocked TGF--stimulated collagen gene expression but expression of an active mutant of MEK was additive with TGF- treatment. Thus, cAMP elevating agents inhibit the profibrotic effects of TGF- in cardiac fibroblasts largely through inhibiting ERK1/2 phosphorylation but also by reducing Smad-mediated recruitment of transcriptional co-activators.
Key words:
Adrenergic, Adenylyl cyclases, cAMP, MAP Kinase
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