Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart.
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.
Wang
Baiqiu
B
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6.
Hao
Jianming
J
Jones
Stephen C
SC
Yee
May-Sann
MS
Roth
Julie C
JC
Dixon
Ian M C
IM
D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D012097:Repressor Proteins; D051899:Smad2 Protein; D051906:Smad7 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D024061:Collagen Type III; D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051906:Smad7 Protein; C497808:Smad7 protein, rat; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1