Abstract 4365727: The role of fibroblast activation protein on left ventricular geometry, growth and extracellular matrix remodeling with pressure overload

Abstract

Background: Fibroblast activation protein (FAP) is abundantly expressed in cancer associated fibroblasts and contributes to extracellular matrix (ECM) remodeling. However, the role of FAP in terms of left ventricular (LV) structure and function, particularly with a chronic pressure overload (LVPO) remained unknown. This project tested the hypothesis that genetic ablation of FAP would modify LV structure and function with LVPO and be associated with changes in ECM remodeling. Methods and Results: Mice with FAP gene deletion (FAPKO, C57BL/6 background, ~13 and 20 weeks of age, with equal sex distribution) and age matched wild type (WT, equal sex distribution) underwent LV echocardiography (Baseline) and then were randomized to LVPO (transverse aortic constriction) for 28 days or referent control (No-LVPO) whereby LV function studies were repeated. Sample sizes and results are shown in Table. While LV ejection fraction (LVEF) fell slightly in both LVPO groups, this change was similar with WT and FAPKO. However, LV end-diastolic volume (LVEDV) was higher with LVPO in the FAPKO group. LV mass increased in both LVPO groups but was increased with FAPKO. Histomorphometry revealed increased myocyte cross sectional area (CSA) and percent collagen in both LVPO groups, but higher with FAPKO. Interestingly, LV hypertrophy and fibrosis also occurred with FAPKO in the absence of LVPO. At the transcriptional level (rtPCR) natriuretic peptide B (NPPB) mRNA levels were higher with LVPO in the FAPKO group as were collagen Type I levels (Col1A) and the tissue inhibitor of the matrix metalloproteinase-1 (TIMP-1). Conclusions: FAP gene deletion resulted in greater LV dilation, fibrosis and natriuretic peptide expression suggestive of acceleration of LV failure. FAP deletion with LVPO caused increased ECM expression and reduced indices of ECM turnover. Modulating FAP expression/activity with LVPO holds a novel therapeutic direction.