Published online before print June 24, 2004, doi: 10.1161/01.RES.0000136520.07995.aa
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Valvular Myofibroblast Activation by Transforming Growth Factor-ß
Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease
From the Department of Molecular, Cellular, and Developmental Biology (G.A.W., L.A.L.) and the Department of Chemical Engineering and the Howard Hughes Medical Institute (K.S.M., D.N.S., K.S.A.), University of Colorado, Boulder.
Correspondence to Dr Leslie A. Leinwand, Department of Molecular, Cellular, and Developmental Biology, Campus Box 347, University of Colorado, Boulder, CO 80309. E-mail Leslie.Leinwand{at}colorado.edu
The pathogenesis of cardiac valve disease correlates with the emergence of muscle-like fibroblasts (myofibroblasts). These cells display prominent stress fibers containing 
-smooth muscle actin (-SMA) and are believed to differentiate from valvular interstitial cells (VICs). However, the biological factors that initiate myofibroblast differentiation and activation in valves remain unidentified. We show that transforming growth factor-ß1 (TGF-ß1) mediates differentiation of VICs into active myofibroblasts in vitro in a dose-dependent manner, as determined by a significant increase in -SMA and the dramatic augmentation of stress fiber formation and alignment. Additionally, TGF-ß1 and increased mechanical stress function synergistically to enhance contractility. In turn, contractile valve myofibroblasts exert tension on the extracellular matrix, resulting in a dramatic realignment of extracellular fibronectin fibrils. TGF-ß1 also inhibits valve myofibroblast proliferation without enhancing apoptosis. Our results are consistent with activation of a highly contractile myofibroblast phenotype by TGF-ß1 and are the first to connect valve myofibroblast contractility with pathological valve matrix remodeling. We suggest that the activation of contractile myofibroblasts by TGF-ß1 may be a significant first step in promoting alterations to the valve matrix architecture that are evident in valvular heart disease.
Key Words: valvular heart disease • valvular interstitial cells • myofibroblasts • TGF-ß1 • -smooth muscle actin • contractility
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