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Valvular myofibroblast activation by tra ... modeling in heart valve disease
Valvular myofibroblast activation by transforming growth factor-beta: implications for pathological extracellular matrix remodeling in heart valve disease.
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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.
Walker GA, Masters KS, Shah DN, Anseth KS, Leinwand LA
Circulation research
2004-08-06 00:00
95
3
253-60
Actins,Animals,Apoptosis,Cell Differentiation,Cell Division,Cells, Cultured,Collagen,DNA Replication,Extracellular Matrix,Fibroblasts,Gene Expression Regulation,Heart Valves,Promoter Regions (Genetics),Rats,Stress Fibers,Stress, Mechanical,Swine,Actins,Collagen
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
Circ. Res.
NIGMS GM-29090
1524-4571
10.1161/01.RES.0000136520.07995.aa
01.RES.0000136520.07995.aa
797
True
15217906
