@article{10902/34953,
year = {2013},
url = {https://hdl.handle.net/10902/34953},
abstract = {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.},
organization = {Funding: This work was supported by: Instituto de Salud Carlos III (PS09/ 01097); Fundación Marqués de Valdecilla-Universidad de Cantabria (FMV-UC 09/01); Instituto de Formación e Investigación Marqués de Valdecilla (FMV-API 10/20); and Ministerio de Ciencia e Innovación (SAF2010-16894). Acknowledgements: We acknowledge the technical assistance of Nieves García, Ana Cayón, Amalia Cavayé, Elena Martín, RN, Roberto Moreta, RN, and Ana Sandoval.},
publisher = {Elsevier},
publisher = {Biochimica et Biophysica Acta. Molecular Basis of Disease, 2013, 1832(2), 323-35},
title = {BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-ß signaling},
author = {Villar Ramos, Ana Victoria and García López, Raquel and Llano, Miguel and Cobo, Manuel and Merino, David and Lantero, Aquilino and Tramullas Fernández, Mónica and Hurlé González, Juan M. and Hurlé González, María Amor and Nistal Herrera, Juan Francisco},
}