Abstract 14298: The Normal Balance Between Antifibrotic Bmp-7 and Profibrotic Tgf-β Signaling is Lost on the Pressure Overload-induced LV Remodeling and Can Be Modified Favorably. A Translational Study
Introduction: Cytokynes of the Transforming Growth Factor-β(TGF-β) superfamily are involved in tissue fibrosis: TGF-β promotes fibrosis, whereas Bone Morphogenetic Protein-7 (BMP-7) is antifibrotic. Hypothesis: (i) LV remodeling in the pressure overload condition associates disequilibrium in the cellular signals mediated by these cytokynes; and (ii) BMP-7 exerts beneficial effects on LV remodeling and on reverse remodeling.
Methods: We studied patients with aortic stenosis (AS; n=45) and surgical controls (n=30), and mice subjected to transverse aortic constriction (TAC; n=24). LV morphology and function were assessed by echocardiography; LV samples were analyzed by qPCR, immunoblotting and histology.
Results: Pressure overload diminished the expression of BMP-7 and its effectors pSmad1/5/8 and increased the ratio TGF-β/BMP-7 in the LV from AS-patients and TAC-mice. BMP-7 expression correlated inversely with collagens, fibronectin and β-myosin heavy chain, with the degree of hypertrophy, and with the severity of diastolic dysfunction, and directly with systolic function. Multiple linear regression analysis disclosed BMP-7 and TGF-β as predictors, negative and positive, respectively, of hypertrophy. BMP-7 prevented the hypertrophic program elicited by TGF-β in cultured cardiomyocytes, and the transcriptional activation of Col1A1 promoter-luciferase reporter in NIH-3T3 fibroblasts. In TAC-mice, BMP-7 gain-of-function attenuated the development of structural damage and dysfunction, halted ongoing remodeling and facilitated reverse remodeling. BMP-7 loss-of-function exerted opposite effects. Luciferase reporter assays in NIH-3T3 fibroblasts suggested that BMP-7 promoted the transcription of the inhibitory Smad7, who in turn has a repressing effect on TGFβ signaling. Accordingly, in AS-patients and TAC-mice, the LV expressions of Smad7 and BMP-7 correlated directly.
Conclusion: The disequilibrium between BMP-7 and TGF-β signals plays a relevant role in the pressure overload-induced myocardial remodeling in TAC-mice and AS-patients. We suggest that BMP-7 antagonizes the hypertrophic and profibrogenic effects of TGF-β through a mechanism involving Smad7. Funding: PI12/00999; RD12/0042/0018; RD12/0042/0012.
Author Disclosures: F. Nistal: None. D. Merino: None. A.V. Villar: None. R. Garcia-Lopez: None. M. Tramullas: None. L. Ruiz-Guerrero: None. C. Ribas: None. M.A. Hurle: None.
- © 2015 by American Heart Association, Inc.