Eintrag weiter verarbeiten
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....
Gespeichert in:
| Zeitschriftentitel: | Circulation |
|---|---|
| Personen und Körperschaften: | , , , , , , , |
| In: | Circulation, 132, 2015, suppl_3 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Ovid Technologies (Wolters Kluwer Health)
|
| Schlagwörter: |
| Zusammenfassung: | <jats:p> <jats:bold>Introduction:</jats:bold> 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. </jats:p> <jats:p> <jats:bold>Methods:</jats:bold> 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. </jats:p> <jats:p> <jats:bold>Results:</jats:bold> 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. </jats:p> <jats:p> <jats:bold>Conclusion:</jats:bold> 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. </jats:p> |
|---|---|
| ISSN: |
0009-7322
1524-4539 |
| DOI: | 10.1161/circ.132.suppl_3.14298 |