title: Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro.
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.
authors.affiliation: Laboratory of Molecular Cardiology, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6.
authors.forename: J
authors.initials: J
authors.lastname: Hao
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: S C
authors.initials: SC
authors.lastname: Jones
authors.forename: D S
authors.initials: DS
authors.lastname: Jassal
authors.forename: I M
authors.initials: IM
authors.lastname: Dixon
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D051899:Smad2 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000096:biosynthesis; D014746:Vimentin / Q000032:analysis
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D004268:DNA-Binding Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051901:Smad4 Protein; C490811:Smad4 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014746:Vimentin; D000804:Angiotensin II; D003094:Collagen; D019808:Losartan