Genetic ablation of fibroblast activation protein alpha attenuates left ventricular dilation after myocardial infarction

Abstract

Introduction Regulating excessive activation of fibroblasts may be a promising target to optimize extracellular matrix deposition and myocardial stiffness. Fibroblast activation protein alpha (FAP) is upregulated in activated fibroblasts after myocardial infarction (MI), and alters fibroblast migration in vitro. We hypothesized that FAP depletion may have a protective effect on left ventricular (LV) remodeling after MI. Materials and methods We used the model of chronic MI in homozygous FAP deficient mice (FAP-KO, n = 51) and wild type mice (WT, n = 55) to analyze wound healing by monocyte and myofibroblast infiltration. Heart function and remodeling was studied by echocardiography, morphometric analyses including capillary density and myocyte size, collagen content and in vivo cell-proliferation. In non-operated healthy mice up to 6 months of age, morphometric analyses and collagen content was assessed (WT n = 10, FAP-KO n = 19). Results Healthy FAP-deficient mice did not show changes in LV structure or differences in collagen content or cardiac morphology. Infarct size, survival and cardiac function were not different between FAP-KO and wildtype mice. FAP-KO animals showed less LV-dilation and a thicker scar, accompanied by a trend towards lower collagen content. Wound healing, assessed by infiltration with inflammatory cells and myofibroblasts were not different between groups. Conclusion We show that genetic ablation of FAP does not impair cardiac wound healing, and attenuates LV dilation after MI in mice. FAP seems dispensable for normal cardiac function and homeostasis.

Circulating fibroblast activation protein α is reduced in acute ischemic stroke

“…FAP has dipeptidyl peptidase and endopeptidase activities, its substrates are largely unknown ( 22 ). Preclinical models targeting FAP show that FAP knockout is not associated with disease ( 23 , 24 ) Circulating FAP cleaves alpha2-antiplasmin, which thereby becomes a potent inhibitor of plasmin, leading to a reduction in fibrinolysis ( 22 ). This fact supports our findings by higher NIHSS scores in patients with lower FAP concentrations.…”

A clinical study on relationship between visualization of cardiac fibroblast activation protein activity by Al18F-NOTA-FAPI-04 positron emission tomography and cardiovascular disease

“…In contrast, some results suggest The ROC curve for predicting calcified plaques by myocardial FAPI uptake (SUV mean ) in LAD, LCX, and RCA territory showed areas under the curve (AUCs) were 0.786 (95%CI: 0.581-0.99), 0.759 (95%CI: 0.521-0.998), and 0.769 (95%CI: 0.559-0.978), respectively. that FAP is not crucial for cell proliferation, adherence and migration within the myocardium after MI (8). The lack of noninvasive tools that can monitor fibroblast activation in humans, however, has limited the success of translating these results to human patients.…”

“…After the coronary injury, Varasteh et al showed that 68 Ga-FAPI uptake peaked at day 6 post-MI, most of which occurred in the border-ischemic area ( 5 ). In contrast, some results suggest that FAP is not crucial for cell proliferation, adherence and migration within the myocardium after MI ( 8 ). The lack of non-invasive tools that can monitor fibroblast activation in humans, however, has limited the success of translating these results to human patients.…”

“…Both diabetes mellitus and transaortic constriction promote cardiomyocyte hypertrophy and excessive cardiac fibrosis based on animal studies ( 37 , 38 ). According to these models, cardiac fibrosis is caused by activated inflammatory pathways and TGFβ/Mothers Against Decapentaplegic Homolog Protein signaling ( 8 , 35 ). There may be a simultaneous dysregulation of metabolic and hypertrophic pathways in the human heart responsible for the increase in FAPI uptake.…”

“…It has been proven to be useful in a variety of tumor imaging applications ( 7 ). In previous studies, FAPI-04 has been shown to be a promising radiotracer of post-MI fibroblast activation ( 5 , 8 – 11 ), or may provide a novel biomarker of left ventricular remodeling that is complementary to existing techniques such as MRI ( 12 , 13 ). In this study, we aimed to compare FAPI tracer accumulation and the benefit of FAPI PET/CT scans in patients with various CVD risk factors and whether can assist in evaluating the degree of fibrosis of coronary artery plaques.…”