Abstract 17085: Recombinant Glial Growth Factor-2 Selectively Modifies Post-myocardial Infarction Fibroblast Form and Function
Background: Left ventricular (LV) remodeling occurs following a myocardial infarction (MI), which includes changes in the myocardial and extracellular matrix (ECM) domains, and determines the extent of heart failure progression. LV fibroblasts (FIBROs) regulate the ECM and thus represent a cellular target for modifying post-MI remodeling. Neuregulin-1beta (NG-1) is a growth factor that regulates neonatal LV development and delivery of the full-length recombinant NG-1 Glial Growth Factor-2 (GGF2) has been shown to alter post-MI remodeling. However, the effects of GGF2 on LV FIBROs, particularly post-MI FIBROs in terms of phenotype and determinants of ECM remodeling, remain unknown.
Methods and Results: LV FIBROs were isolated from normal adult pigs (n=6) and post-MI pigs (14 days, coronary occlusion, n=6) and FIBRO function (3-D collagen gel contraction rate, ECM adhesion) and gene expression (PCR arrays) with and without exposure to GGF2 (175 ng/mL/24 hrs). GGF2 reduced post-MI FIBRO gel contraction (49±2%, p<0.05; 8hrs) and ECM adhesion (33±7%, p<0.05; 24 hrs), but not in normal FIBROs. GGF2 differentially induced FIBRO collagen VI expression in normal vs post-MI (36±13 vs 3±10%, p<0.05) and altered expression of determinants of ECM remodeling only in post-MI FIBROs (Table). Using targeted PCR, the predominant NG-1/GGF2 receptor, ErbB4, was increased by over 2-fold in post-MI vs control FIBROs (p<0.05).
Conclusions: The novel findings of this study demonstrated that post-MI FIBROs, a critical cellular determinant of ECM remodeling, are sensitive and responsive to recombinant GGF2. These studies demonstrate that selective targeting of post-MI FIBROs through specific growth signaling pathways, such as NG-1, is feasible and may favorably alter adverse ECM remodeling post-MI.
Author Disclosures: E.C. Goldsmith: None. H. Doviak: None. P.E. Perreault: None. K.R. Swimmer: None. K.N. Zellars: None. J. Jacobs: None. J. Iaci: Employment; Significant; Acorda. Other; Significant; Acorda stockholder. H. O’Neil: Employment; Significant; Acorda. Other; Significant; Acorda stockholder. A.O. Caggiano: Employment; Significant; Acorda. Other; Significant; Acorda stockholder. F.G. Spinale: Research Grant; Significant; NIH. Consultant/Advisory Board; Modest; Boston Scientific, Novartis, Amgen.
- © 2016 by American Heart Association, Inc.