Abstract
Angiotensin II (angiotensin) and transforming growth factor (TGF)-beta(1) play an important role in cardiac fibrosis. We examined Smad proteins in 8-wk post-myocardial infarction (MI) rat hearts. AT(1) blockade (losartan) attenuated the activation of TGF-beta(1) in target tissues. Losartan administration (8 wk, 15 mg. kg(-1). day(-1)) normalized total Smad 2 overexpression in infarct scar and remnant heart tissue and normalized Smad 4 in infarct scar. Phosphorylated Smad 2 (P-Smad 2) staining decreased in cytosol from failing heart vs. the control, which was normalized by losartan, suggesting augmented P-Smad 2 movement into nuclei in untreated failing hearts. Using adult primary rat fibroblasts treated with angiotensin (10(-6) M), we noted rapid translocation (15 min) of P-Smad 2 into the nuclei from the cytosol. Nuclear P-Smad 2 protein level increased with angiotensin treatment, which was blocked by losartan. We conclude that angiotensin may influence total Smad 2 and 4 expression in post-MI heart failure and that angiotensin treatment is associated with rapid P-Smad 2 nuclear translocation in isolated fibroblasts. This study suggests that cross talk between angiotensin and Smad signaling is associated with fibrotic events in post-MI hearts.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology
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Angiotensin II / metabolism*
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Angiotensin Receptor Antagonists
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Animals
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Antihypertensive Agents / pharmacology
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Cardiomegaly / metabolism
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Cardiomegaly / pathology
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Cell Nucleus / chemistry
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Cell Nucleus / metabolism
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Cells, Cultured
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Collagen / analysis
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Cytosol / chemistry
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Cytosol / metabolism
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / metabolism*
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Fibroblasts / chemistry
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Heart Failure / metabolism
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Heart Failure / pathology
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In Vitro Techniques
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Losartan / pharmacology
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Male
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Myocardial Infarction / metabolism*
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Myocardial Infarction / pathology
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Myocardium / chemistry
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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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Receptor Cross-Talk / physiology
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin / metabolism
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Smad2 Protein
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Smad4 Protein
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Trans-Activators / analysis
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Trans-Activators / metabolism*
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Transforming Growth Factor beta / analysis
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Transforming Growth Factor beta / biosynthesis
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Vimentin / analysis
Substances
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Angiotensin Receptor Antagonists
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Antihypertensive Agents
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DNA-Binding Proteins
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Receptor, Angiotensin, Type 1
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Receptor, Angiotensin, Type 2
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Receptors, Angiotensin
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Smad2 Protein
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Smad2 protein, rat
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Smad4 Protein
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Smad4 protein, rat
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Trans-Activators
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Transforming Growth Factor beta
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Vimentin
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Angiotensin II
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Collagen
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Losartan