BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-ß signaling
Left ventricular (LV) pressure overload is a major cause of heart failure. Transforming growth factors-beta (TGF-betas) promote LV remodeling under biomechanical stress. BAMBI (BMP and activin membrane-bound inhibitor) is a pseudoreceptor that negatively modulates TGF-beta signaling. The present stu...
| Authors: | , , , , , , , , , |
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| Format: | article |
| Publication Date: | 2013 |
| Country: | España |
| Institution: | Universidad de Cantabria (UC) |
| Repository: | UCrea Repositorio Abierto de la Universidad de Cantabria |
| Language: | English |
| OAI Identifier: | oai:repositorio.unican.es:10902/34953 |
| Online Access: | https://hdl.handle.net/10902/34953 |
| Access Level: | Open access |
| Keyword: | Myocardial remodeling Aortic valve stenosis Pressure overload TGF-β BAMBI miR-21 |
| Summary: | Left ventricular (LV) pressure overload is a major cause of heart failure. Transforming growth factors-beta (TGF-betas) promote LV remodeling under biomechanical stress. BAMBI (BMP and activin membrane-bound inhibitor) is a pseudoreceptor that negatively modulates TGF-beta signaling. The present study tests the hypothesis that BAMBI plays a protective role during the adverse LV remodeling under pressure overload. The subjects of the study were BAMBI knockout mice (BAMBI(-/-)) undergoing transverse aortic constriction (TAC) and patients with severe aortic stenosis (AS). We examined LV gene and protein expression of remodeling-related elements, histological fibrosis, and heart morphology and function. LV expression of BAMBI was increased in AS patients and TAC-mice and correlated directly with TGF-beta. BAMBI deletion led to a gain of myocardial TGF-beta signaling through canonical (Smads) and non-canonical (TAK1-p38 and TAK1-JNK) pathways. As a consequence, the remodeling response to pressure overload in BAMBI(-/-) mice was exacerbated in terms of hypertrophy, chamber dilation, deterioration of long-axis LV systolic function and diastolic dysfunction. Functional remodeling associated transcriptional activation of fibrosis-related TGF-beta targets, up-regulation of the profibrotic micro-RNA-21, histological fibrosis and increased metalloproteinase-2 activity. Histological remodeling in BAMBI(-/-) mice involved TGF-betas. BAMBI deletion in primary cardiac fibroblasts exacerbated TGF-beta-induced profibrotic responses while BAMBI overexpression in NIH-3T3 fibroblasts attenuated them. Our findings identify BAMBI as a critical negative modulator of myocardial remodeling under pressure overload. We suggest that BAMBI is involved in negative feedback loops that restrain the TGF-beta remodeling signals to protect the pressure-overloaded myocardium from uncontrolled extracellular matrix deposition in humans and mice. |
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