title: BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-β signaling.
abstract: Left ventricular (LV) pressure overload is a major cause of heart failure. Transforming growth factors-β (TGF-βs) promote LV remodeling under biomechanical stress. BAMBI (BMP and activin membrane-bound inhibitor) is a pseudoreceptor that negatively modulates TGF-β 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-β. BAMBI deletion led to a gain of myocardial TGF-β 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-β targets, up-regulation of the profibrotic micro-RNA-21, histological fibrosis and increased metalloproteinase-2 activity. Histological remodeling in BAMBI(-/-) mice involved TGF-βs. BAMBI deletion in primary cardiac fibroblasts exacerbated TGF-β-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-β remodeling signals to protect the pressure-overloaded myocardium from uncontrolled extracellular matrix deposition in humans and mice.
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Ana V
authors.initials: AV
authors.lastname: Villar
authors.forename: Raquel
authors.initials: R
authors.lastname: García
authors.forename: Miguel
authors.initials: M
authors.lastname: Llano
authors.forename: Manuel
authors.initials: M
authors.lastname: Cobo
authors.forename: David
authors.initials: D
authors.lastname: Merino
authors.forename: Aquilino
authors.initials: A
authors.lastname: Lantero
authors.forename: Mónica
authors.initials: M
authors.lastname: Tramullas
authors.forename: Juan M
authors.initials: JM
authors.lastname: Hurlé
authors.forename: María A
authors.initials: MA
authors.lastname: Hurlé
authors.forename: J Francisco
authors.initials: JF
authors.lastname: Nistal
mesh_terms: D000818:Animals; D055028:Comparative Genomic Hybridization; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013312:Stress, Physiological; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C485672:Bambi protein, mouse; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta