title: Differential and combined effects of cardiotrophin-1 and TGF-beta1 on cardiac myofibroblast proliferation and contraction.
abstract: Myofibroblasts respond to an array of signals from mitogens and cytokines during the course of wound healing following a myocardial infarction (MI), and these signals may coordinate ventricular myofibroblast proliferation. Furthermore, myofibroblasts are contractile and contribute to wound contraction by imparting mechanical tension on surrounding extracellular matrix. Although TGF-beta(1), CT-1, and PDGF-BB participate in various stages of post-MI wound healing, their combined net effect(s) on myofibroblast function is unknown. We investigated myofibroblast proliferation, expression of cell cycle proteins, and contractile function of cells treated with TGF-beta(1) and/or CT-1. We confirmed that TGF-beta(1) (10 ng/ml) suppresses proliferation of these cells, whereas CT-1 (10 ng/ml) and, for comparative purposes, PDGF-BB (1 ng/ml) treatments were associated with proliferation. Specific TGF-beta(1) treatment ablated CT-1-induced myofibroblast proliferation. TGF-beta(1) effects were specific, as they were suppressed by either TGF-beta-neutralizing antibody or viral Smad7 overexpression. TGF-beta(1) treatment also increased expression of p27 and decreased expression of cyclin E and Cdk2 in primary cells. CT-1 (10 ng/ml) treatment of myofibroblasts had no effect on collagen gel deformation versus controls, whereas TGF-beta(1) (10 ng/ml) and PDGF (10 ng/ml) treatments were associated with significant cell contraction; again, TGF-beta(1)-mediated contraction was unaffected by CT-1. Alone, CT-1 and TGF-beta(1) treatments exert opposing effects on myofibroblast function, whereas in combination TGF-beta(1)-mediated effects supersede those of CT-1 (and PDGF-BB). Thus TGF-beta(1) and CT-1 exert differential effects on myofibroblast proliferation and contraction in vitro, and we suggest that a balance of these effects may be important for the execution of normal cardiac wound healing.
authors.affiliation: Institute of Cardiovascular Science, St. Boniface General Hospital Research Centre, Department of Physiology, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Vanja
authors.initials: V
authors.lastname: Drobic
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Cunnington
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Bedosky
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Raizman
authors.forename: Vinit V
authors.initials: VV
authors.lastname: Elimban
authors.forename: Sunil G
authors.initials: SG
authors.lastname: Rattan
authors.forename: Ian M C
authors.initials: IM
authors.lastname: Dixon
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005782:Gels; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D014945:Wound Healing
chemical_list: C493962:Cdkn1b protein, rat; D024042:Collagen Type I; D019927:Cyclin E; D016207:Cytokines; D005782:Gels; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D053773:Transforming Growth Factor beta1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; C092073:cardiotrophin 1; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2