TGFß Signaling via ERK1/2 and Smad is Inhibited by cAMP-Elevating Agents in Rat Cardiac Fibroblasts

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Cardiac fibroblasts (CF) play a central role in the maintenance of extracellular matrix in the normal heart and in inflammatory and fibrotic myocardial remodeling in the injured or failing heart. Cytokines such as transforming growth factor-ß (TGFß) play a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and other pro-fibrotic responses. Agents that elevate cAMP production appear to inhibit TGFß stimulation of CF but the mechanism by which this occurs is unknown. The goal of this study was to understand the signaling pathways by which cAMP-elevating agents inhibit collagen expression and myofibroblast differentiation. Treatment with 10 μM forskolin or 10 μM isoproterenol increased cAMP production and inhibited serum- or TGFß-stimulated collagen synthesis and myofibroblast differentiation (assessed as α-smooth muscle actin expression). These same cAMP-elevating agents blunted TGFß-induced activation of ERK1/2 as well as collagen I and collagen III gene expression. Forskolin and isoproterenol also reduced binding of the transcriptional co-activator CBP-1 to Smad transcriptional complexes. However, pharmacological inhibition of ERK1/2 activation completely blocked TGFß-stimulated collagen gene expression. Thus, cAMP elevating agents inhibit the profibrotic effects of TGFß in cardiac fibroblasts primarily by inhibiting ERK1/2 activation but also by reducing Smad-mediated recruitment of transcriptional coactivators. Increasing cAMP levels in CF may be a useful therapeutic strategy in treating the fibrotic component of heart disease.


This abstract was originally published in FASEB Journal, volume 20, issue 5, in 2006.


Federation of American Society of Experimental Biology (FASEB)