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.

Transcriptional Repression of the Transforming Growth Factor β (TGF-β) Pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 Enhances TGF-β Signaling in Hepatic Stellate Cells

“…Several investigators have recognized the important role of BAMBI in recent years. BAMBI protects the murine heart from pressure overload biomechanical stress by restraining TGF-␤ signaling (20). BAMBI has also been reported as a negative regulator of adipogenesis and modulator of the antiand proadipogenic effects of TGF-␤ (21).…”

The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells

“…Expression of ALK4/5 ligands leads to the activation of fibroblasts in cardiac tissue by promoting myofibroblast differentiation, enhancing the synthesis of extracellular matrix proteins and regulating fibrotic remodeling of the diseased heart in a variety of conditions [11-14]. Inhibition of the TGF-β pathway alleviates left ventricular remodeling, systolic and diastolic dysfunction [15-17]. Although a key role for TGF-β in fibrotic cardiac remodeling has been established, its vascular effects have not been examined.…”

Vessel wall BAMBI contributes to hemostasis and thrombus stability

“…37 An enhanced angiogenic response in vivo using Matrigel implants was also observed. 37 A role for BAMBI in some of the remodeling processes following heart pressure overload 38 and mechanical injury of the femoral artery has also been reported, 39 although how these phenotypes are conferred is still unclear.…”

“…10,12,13,[36][37][38]52 Of particular interest, Bambi 2/2 mice have an apparent increased angiogenic potential, 37 and exacerbated remodeling in response to heart pressure overload. 38 Both of these studies implicated alteration of the TGFb signaling pathway (canonical and noncanonical) in EC and primary cardiac fibroblasts, respectively. Platelets contain large amounts of latent TGFb1 in their a-granules (;40-1003 more than other cell types) 53 that is released upon platelet activation.…”