期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1832, 期 2, 页码 323-335出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2012.11.007
关键词
Myocardial remodeling; Aortic valve stenosis; Pressure overload; TGF-beta; BAMBI; miR-21
资金
- Instituto de Salud Carlos III [PS09/01097]
- Fundacion Marques de Valdecilla-Universidad de Cantabria [FMV-UC 09/01]
- Instituto de Formacion e Investigacion Marques de Valdecilla [FMV-API 10/20]
- Ministerio de Ciencia e Innovacion [SAF2010-16894]
Left ventricular (LV) pressure overload is a major cause of heart failure. Transforming growth factors-beta (TGF-beta s) 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 again 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-beta s. 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. (C) 2012 Elsevier B.V. All rights reserved.
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