Soluble transforming growth factor-beta1 receptor II might inhibit transforming growth factor-beta-induced myofibroblast differentiation and improve ischemic cardiac function after myocardial infarction in rats.
OBJECTIVE
Cardiac fibroblasts (CFs) regulate myocardial fibrosis and remodeling through proliferation and differentiation. Transforming growth factor-beta1 (TGF-beta1) plays a critical role in the development of myocardial fibrosis after myocardial infarction (MI). The aim of this study was to investigate the effects of inhibiting TGF-beta1 action on myofibroblast differentiation and cardiac function after MI.


METHODS
CFs were cultured and treated, respectively with PBS, TGF-beta1, soluble TGF-beta1 receptor II (sTbetaRII), and TGF-beta1 plus sTbetaRII. Proliferation CFs were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Myofibroblast differentiation was examined by alpha-smooth muscle actin immunostaining. Expression of P-Smad2 and Smad2/3 was determined by immunostaining and western blot analysis. Four days after ligation of left anterior descending coronary artery, sTbetaRII was injected into injured heart. Two weeks after sTbetaRII administration, myofibroblast differentiation was measured with alpha-smooth muscle actin immunostaining. Four weeks after sTbetaRII administration, cardiac function was evaluated by hemodynamic measurements. Weight parameters, infarct size, and collagen fiber were detected with an earlier experimental method.


RESULTS
Compared with TGF-beta1, TGF-beta1 plus sTbetaRII significantly decreased cell proliferation, myofibroblast differentiation, and expression of P-Smad2 in CFs (P<0.05). Two weeks after sTbetaRII administration, myofibroblast differentiation in MI rats treated with sTbetaRII was reduced compared with MI group (P<0.05). Four weeks after sTbetaRII administration, MI rats that received sTbetaRII showed significantly higher cardiac function and lower in weight parameters, infarct size, and collagen fiber than that of MI group (P<0.05).


CONCLUSIONS
sTbetaRII could inhibit TGF-beta1-induced myofibroblast differentiation, alleviate myocardial fibrosis and remodeling, and improve ischemic cardiac function after MI.
Lian
Ruiqing
R
Department of Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College bSchool of Medicine, Tsinghua University, Beijing, China.
Chen
Yuejie
Y
Xu
Zenglu
Z
Zhang
Xiaodong
X
D000199:Actins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D007150:Immunohistochemistry; D008845:Microinjections; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage*; D020127:Recovery of Function; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
D000199:Actins; D002317:Cardiovascular Agents; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C497784:Smad2 protein, rat; C497787:Smad3 protein, rat; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat