Differential and combined effects of cardiotrophin-1 and TGF-beta1 on cardiac myofibroblast proliferation and contraction

Institute of Cardiovascular Science, St. Boniface General Hospital Research Centre, Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada Submitted 29 August 2006 ; accepted in final form 30 April 2007 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- 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- 1 and/or CT-1. We confirmed that TGF- 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- 1 treatment ablated CT-1-induced myofibroblast proliferation. TGF- 1 effects were specific, as they were suppressed by either TGF- -neutralizing antibody or viral Smad7 overexpression. TGF- 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- 1 (10 ng/ml) and PDGF (10 ng/ml) treatments were associated with significant cell contraction; again, TGF- 1 -mediated contraction was unaffected by CT-1. Alone, CT-1 and TGF- 1 treatments exert opposing effects on myofibroblast function, whereas in combination TGF- 1 -mediated effects supersede those of CT-1 (and PDGF-BB). Thus TGF- 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. transforming growth factor- 1 ; Smad7 Address for reprint requests and other correspondence: I. M. C. Dixon, Professor of Physiology, Institute of Cardiovascular Science, St. Boniface General Hospital Research Centre, 351 Tache Ave., Winnipeg, MB, Canada R2H 2A6 (e-mail: idixon{at}sbrc.ca )