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BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-ß signaling

Abstract: Left ventricular (LV) pressure overload is a major cause of heart failure. Transforming growth factors-? (TGF-?s) promote LV remodeling under biomechanical stress. BAMBI (BMP and activin membrane-bound inhibitor) is a pseudoreceptor that negatively modulates TGF-? 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-?. BAMBI deletion led to a gain of myocardial TGF-? 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-? targets, up-regulation of the profibrotic micro-RNA-21, histological fibrosis and increased metalloproteinase-2 activity. Histological remodeling in BAMBI(-/-) mice involved TGF-?s. BAMBI deletion in primary cardiac fibroblasts exacerbated TGF-?-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-? remodeling signals to protect the pressure-overloaded myocardium from uncontrolled extracellular matrix deposition in humans and mice.

 Autoría: Villar A., García R., Llano M., Cobo M., Merino D., Lantero A., Tramullas M., Hurlé J., Hurlé M., Nistal J.,

 Fuente: Biochimica et Biophysica Acta. Molecular Basis of Disease, 2013, 1832(2), 323-35

 Editorial: Elsevier

 Año de publicación: 2013

 Nº de páginas: 13

 Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.bbadis.2012.11.007

 ISSN: 0925-4439,1879-260X

 Proyecto español: SAF2010-16894

 Url de la publicación: http://dx.doi.org/10.1016/j.bbadis.2012.11.007

Autoría

GARCÍA, RAQUEL

LLANO, MIGUEL

COBO, MANUEL

MERINO, DAVID

LANTERO, AQUILINO