Abstract
We examined the role of the transforming growth factor (TGF)-beta(1) signaling inhibitor Smad 7 in cardiac fibrosis. TGF-beta(1) (10 ng/ml) was found to increase cytosolic Smad 7 expression in primary adult rat fibroblasts and induce rapid nuclear export of exogenous Smad 7 in COS-7 cells. Furthermore, overexpression of Smad 7 in primary adult fibroblasts was associated with suppressed collagen type I and III expression. We detected Smad 7, phosphorylated Smad 2, TGF-beta type I receptor (TbetaRI), and TGF-beta(1) proteins in postmyocardial infarct (MI) rat hearts. In 2 and 4 wk post-MI hearts, Smad 7 and TbetaRI expression were decreased in scar tissue, whereas TGF-beta(1) expression was increased in scar and viable tissue. In the 8 wk post-MI heart, Smad 7 expression was decreased in both scar tissue and myocardium remote to the infarct scar. Finally, we confirmed that these changes are paralleled by decreased expression of cytosolic phosphorylated receptor-regulated Smad 2 in 4-wk viable myocardium and in 2- and 4-wk infarct scar tissues. Taken together, our data imply that decreased inhibitory Smad 7 signal in cardiac fibroblasts may play a role in the pathogenesis of cardiac fibrosis in the post-MI heart.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biological Transport
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COS Cells
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Collagen Type I / genetics
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Collagen Type III / genetics
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Cytosol / metabolism
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Fibroblasts / metabolism
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Fibrosis
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Gene Expression*
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Male
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Myocardial Infarction / complications*
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Myocardium / chemistry
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Myocardium / metabolism
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Myocardium / pathology*
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Phosphorylation
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Rats
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Rats, Sprague-Dawley
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Receptors, Transforming Growth Factor beta / analysis
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Repressor Proteins*
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Smad2 Protein
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Smad7 Protein
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Time Factors
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Trans-Activators / analysis
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Trans-Activators / genetics*
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Transfection
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Transforming Growth Factor beta / analysis
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / pharmacology
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Transforming Growth Factor beta1
Substances
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Collagen Type I
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Collagen Type III
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DNA-Binding Proteins
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Receptors, Transforming Growth Factor beta
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Repressor Proteins
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Smad2 Protein
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Smad2 protein, rat
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Smad7 Protein
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Smad7 protein, rat
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Tgfb1 protein, rat
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Trans-Activators
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Transforming Growth Factor beta
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Transforming Growth Factor beta1