期刊
CELLS TISSUES ORGANS
卷 194, 期 1, 页码 1-12出版社
KARGER
DOI: 10.1159/000322035
关键词
Transforming growth factor-beta; Epithelial mesenchymal transformation; Atrioventricular cushion; Heart valve; Receptors
资金
- National Institutes of Health
- Institute of General Medical Sciences [GM007628, GM062459]
- ASPET
- Heart, Lung and Blood Institute [HL092551]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [RL1HL092551] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R25GM062459, T32GM007628] Funding Source: NIH RePORTER
Valvular heart disease is a major cause of mortality and morbidity. Revealing the cellular processes and molecules that regulate valve formation and remodeling is required to develop effective therapies. A key step in valve formation during heart development is the epithelial-mesenchymal transformation (EMT) of a subpopulation of endocardial cells in the atrioventricular cushion (AVC). The type III transforming growth factor-beta receptor (TGF beta R3) regulates AVC endocardial cell EMT in vitro and mesenchymal cell differentiation in vivo. Little is known concerning the signaling mechanisms downstream of TGF beta R3. Here we use endocardial cell EMT in vitro to determine the role of 2 well-characterized downstream TGF beta signaling pathways in TGF beta R3-dependent endocardial cell EMT. Targeting of Smad4, the common mediator Smad, demonstrated that Smad signaling is required for EMT in the AVC and TGF beta R3-dependent EMT stimulated by TGF beta 2 or BMP-2. Although we show that Smads 1, 2, 3, and 5 are required for AVC EMT, overexpression of Smad1 or Smad3 is not sufficient to induce EMT. Consistent with the activation of the Par6/Smurf1 pathway downstream of TGF beta R3, targeting ALK5, Par6, or Smurf1 significantly inhibited EMT in response to either TGF beta 2 or BMP-2. The requirement for ALK5 activity, Par6, and Smurf1 for TGF beta R3-dependent endocardial cell EMT is consistent with the documented role of this pathway in the dissolution of tight junctions. Taken together, our data demonstrate that TGF beta R3-dependent endocardial cell EMT stimulated by either TGF beta 2 or BMP-2 requires Smad4 and the activation of the Par6/Smurf1 pathway. Copyright (C) 2011 S. Karger AG, Basel
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