Abstract 19686: Identification and Putative Function of Fibroblast Activation Protein and Relevance to Post-Myocardial Infarction Remodeling
Background: While changes in extracellular matrix (ECM) structure and function contribute to adverse ventricular (LV) remodeling with myocardial infarction (MI), the integration of cellular (fibroblast; FIBRO) and proteolytic (matrix metalloproteinases, MMPs) with respect to localized activation pathways remains poorly understood. Transformed FIBROs, such as cancer associated FIBROs, have been shown to express a transmembrane serine protease, fibroblast activation protein (FAP). However, whether and to what degree FAP is expressed within the MI, is associated with FIBROs, and functionality in the context of MMP activation remained unclear.
Methods and Results: MI was induced in adult pigs (14 days, coronary ligation, n=5), whereby LV end-diastolic volume increased from baseline (40±1 vs 68±2 mL, p<0.05), consistent with adverse LV remodeling. FAP expression (rtPCR) within the MI increased by 7-fold compared to the identical LV region from referent control pigs (n=4). FIBROs isolated from the MI/control regions expressed robust mRNA levels for FAP, and using confocal microscopy, revealed an induction of FAP within post-MI fibroblasts (Figure Panel A). Using a recombinant FAP and conditioned media from transformed FIBROs (Fibrosarcoma, HT1080) and gelatin zymography, a concentration dependent increase in proteolytic bands, indicative of conversion of pro-MMP-2 to the active form, was observed (performed in duplicate, Figure Panel B; R2=0.83; p≤0.01).
Conclusions: The unique findings from this study are two-fold. First, an upregulation of FAP occurs within the MI region and can be localized to transformed fibroblasts. Second, FAP converted a key ECM protease, MMP-2, to an active form and thus constitutes a new localized mediator of MMP activation within the post-MI myocardium. Since FAP is a transmembrane protease, this constitutes a novel therapeutic target for adverse post-MI remodeling.
Author Disclosures: E.C. Goldsmith: None. H. Doviak: None. P.E. Perreault: None. K.R. Swimmer: None. K.N. Zellars: None. S. Barlow: None. F.G. Spinale: Research Grant; Significant; NIH. Consultant/Advisory Board; Modest; Boston Scientific, Novartis, Amgen, Acorda.
- © 2016 by American Heart Association, Inc.