Fibroblast activation protein modulates left ventricular growth and matrix remodeling

Background: Fibroblast Activation Protein (FAP) is abundantly expressed in cancer associated fibroblasts and contributes to activation of proteolytic cascades which alter extracellular matrix (ECM) remodeling. However, whether and to what degree FAP influences left ventricular (LV) function and myocardial structure remains unclear. The present project tested the hypothesis that genetic ablation of FAP would modify LV structure and function in the absence of a pathological stimulus. Methods and Results: Transgenic mice with FAP gene deletion (FAPKO, C57BL/6 background, 3 months of age, n=24) and age matched wild type (WT, n=24) underwent high fidelity LV echocardiography to measure LV ejection fraction, LV end diastolic volume, and LV mass. All results are reported as mean ± SEM. While LV function (62 ± 1 vs. 65 ± 2 %) and volumes (68 ± 4 vs. 70 ± 4 μL) were within normal limits, LV mass to body weight ratio increased (4.9 ± 0.3 vs. 6.1 ± 0.5 mg/g, p<0.05) in the FAPKO mice. LV myocyte cross sectional area (CSA) (168 ± 24 vs. 210 ± 13 μm2, p<0.05) and collagen content (3.3 ± 0.3 vs. 6.1 ± 0.8%, p=0.07) measured by histomorphometry were increased in FAPKO mice. Using rtPCR, increased levels of collagen type I (1.03 ± 0.07 vs. 1.38 ± 0.19 fold change, p<0.05) and type III (1.04 ± 0.08 vs. 1.74 ± 0.26 fold change, p<0.05) were observed in the FAPKO group. Transforming Growth Factor Beta 2 (TGFβ2) (1.04 ± 0.10 vs. 0.74 ± 0.06 fold change, p<0.05) and Snail Family Transcription Repressor 1 (Snai1) (1.11 ± 0.14 vs. 0.77 ± 0.08 fold change, p<0.05) levels were significantly decreased in the FAPKO mice. Conclusion: Increased LV mass and myocyte CSA accompanied by increased collagen content and expression indicated that LV hypertrophy occurred with genetic deletion of FAP. Shifts in the TGF axis and Snai1 suggests that fibroblast endothelial-mesenchymal transition occurred in the absence of FAP. These findings demonstrated for the first time that FAP, most commonly associated with cancer associated fibroblasts, can alter LV myocardial structure. This work was supported in part by National Institutes of Health grant R01HL130972-01A1 (F.G.S.) & R01HL5949 (F.G.S.) as well as a Merit Award from the Veterans Health Administration, BX000168-10A1 (F.G.S.) & BX005320 (F.G.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.