Abstract 11102: Fibroblast Growth Factor-2 Attenuates Human Cardiac Fibroblast-Mediated Extracellular Matrix Remodeling
BACKGROUND: After MI, elevation of profibrotic transforming growth factor-β1 (TGF-β1) results in myofibroblast-mediated matrix remodeling and progression of heart failure. In this study, we examined the effects of fibroblast growth factor (FGF-2) on human cardiac fibroblast (CF) mediated extracellular matrix (ECM) remodeling.
METHOD/RESULTS: Human CF from atrial or ventricular heart biopsies were seeded into 3D collagen matrices. Myofibroblast activation was functionally assessed by the extent of matrix contraction. As compared to baseline myofibroblast activity, FGF-2 attenuated TGF-β1 mediated myofibroblast activation in both atrial (1.06±0.09 versus 1.17±0.09, P<0.0001) and ventricular fibroblasts (1.12±0.04 vs. 1.51±0.27, P<0.05). New collagen synthesis was assessed by 3H-proline incorporation. Fibroblasts treated with TGF-β1 had increased collagen synthesis while FGF-2 reduced collagen synthesis (P<0.05). ECM dysregulation was investigated by in situ zymography. TGF-β1 increased total protease activity while FGF-2 attenuated this response (2.81±1.1 vs. 0.14±0.45 total florescence units, P<0.01). By quantitative RT-PCR and multiplex analysis, FGF-2 treatment restored tissue inhibitor of metalloproteinase-1 (TIMP) and TIMP-2 gene and protein expression relative to TGF-β1 treated cells (P<0.05 and P<0.01). Fibroblast-mediated ECM remodeling was assessed using thin fixed nylon-based collagen matrices and confocal microscopy. TGF-β1 activated fibroblasts displayed long cell extensions (green, Figure C, E) with compaction of adjacent ECM (red). Addition of FGF-2 attenuated cell activation and ECM remodelling observed with TGF-β1 exposure (Figure D).
CONCLUSIONS: FGF-2 attenuates TGF-β1-mediated human cardiac fibroblast activation and restores ECM homeostasis and regulation. These data provide evidence for FGF-2’s therapeutic potential in preventing maladaptive remodeling and subsequent CHF.
Author Disclosures: D.A. Svystonyuk: None. J.M. Ngu: None. H.E. Mewhort: None. D.G. Guzzardi: None. B.D. Lipon: None. D.S. Park: None. D.D. Belke: None. G. Teng: None. P.W. Fedak: None.
- © 2014 by American Heart Association, Inc.