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  • Title: Valvular myofibroblast activation by transforming growth factor-beta: implications for pathological extracellular matrix remodeling in heart valve disease.
    Author: Walker GA, Masters KS, Shah DN, Anseth KS, Leinwand LA.
    Journal: Circ Res; 2004 Aug 06; 95(3):253-60. PubMed ID: 15217906.
    Abstract:
    The pathogenesis of cardiac valve disease correlates with the emergence of muscle-like fibroblasts (myofibroblasts). These cells display prominent stress fibers containing alpha-smooth muscle actin (alpha-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-beta1 (TGF-beta1) mediates differentiation of VICs into active myofibroblasts in vitro in a dose-dependent manner, as determined by a significant increase in alpha-SMA and the dramatic augmentation of stress fiber formation and alignment. Additionally, TGF-beta1 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-beta1 also inhibits valve myofibroblast proliferation without enhancing apoptosis. Our results are consistent with activation of a highly contractile myofibroblast phenotype by TGF-beta1 and are the first to connect valve myofibroblast contractility with pathological valve matrix remodeling. We suggest that the activation of contractile myofibroblasts by TGF-beta1 may be a significant first step in promoting alterations to the valve matrix architecture that are evident in valvular heart disease.
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