Valvular Myofibroblast Activation by Transforming Growth Factor-β: Implications for Pathological Extracellular Matrix Remodeling in Heart Valve Disease
The pathogenesis of cardiac valve disease correlates with the emergence of muscle-like fibroblasts (myofibroblasts). These cells display prominent stress fibers containing α-smooth muscle actin (α-SMA) and are believed to differentiate from valvular interstitial cells (VICs). However, the biological...
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Veröffentlicht in: | Circulation Research 2004-08, Vol.95 (3), p.253-260 |
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Zusammenfassung: | The pathogenesis of cardiac valve disease correlates with the emergence of muscle-like fibroblasts (myofibroblasts). These cells display prominent stress fibers containing α-smooth muscle actin (α-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-β1 (TGF-β1) mediates differentiation of VICs into active myofibroblasts in vitro in a dose-dependent manner, as determined by a significant increase in α-SMA and the dramatic augmentation of stress fiber formation and alignment. Additionally, TGF-β1 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-β1 also inhibits valve myofibroblast proliferation without enhancing apoptosis. Our results are consistent with activation of a highly contractile myofibroblast phenotype by TGF-β1 and are the first to connect valve myofibroblast contractility with pathological valve matrix remodeling. We suggest that the activation of contractile myofibroblasts by TGF-β1 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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ISSN: | 0009-7330 1524-4571 1524-4539 |
DOI: | 10.1161/01.RES.0000136520.07995.aa |