Deletion of fibroblast activation protein provides atheroprotection

Abstract

Aims Fibroblast activation protein (FAP) is upregulated at sites of tissue remodelling including chronic arthritis, solid tumours, and fibrotic hearts. It has also been associated with human coronary atherosclerotic plaques. Yet, the causal role of FAP in atherosclerosis remains unknown. To investigate the cause-effect relationship of endogenous FAP in atherogenesis, we assessed the effects of constitutive Fap deletion on plaque formation in atherosclerosis-prone apolipoprotein E (Apoe) or low-density lipoprotein receptor (Ldlr) knockout mice. Methods and results Using en face analyses of thoraco-abdominal aortae and aortic sinus cross-sections, we demonstrate that Fap deficiency decreased plaque formation in two atherosclerotic mouse models (-46% in Apoe and -34% in Ldlr knockout mice). As a surrogate of plaque vulnerability fibrous cap thickness was used; it was increased in Fap-deficient mice, whereas Sirius red staining demonstrated that total collagen content remained unchanged. Using polarized light, atherosclerotic lesions from Fap-deficient mice displayed increased FAP targets in terms of enhanced collagen birefringence in plaques and increased pre-COL3A1 expression in aortic lysates. Analyses of the Stockholm Atherosclerosis Gene Expression (STAGE) data revealed that FAP expression was increased in human atherosclerotic compared to non-atherosclerotic arteries. Conclusions Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability with decreased collagen breakdown. Thus, inhibition of FAP expression or activity may not only represent a promising therapeutic target in atherosclerosis but appears safe at the experimental level for FAP-targeted cancer therapies. Translational Perspective Fibroblast activation protein (FAP) is upregulated at sites of chronic tissue remodelling including rheumatoid arthritis and solid tumours. Indeed, depletion of FAP-positive cells inhibits tumour growth by increasing antitumour immunity. FAP has also been correlated with human coronary plaques, whereby its causal role remains unknown. Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability. Thus, inhibition of FAP expression or activity may not only represent a novel therapeutic target for atherosclerosis but appears safe – at the experimental level – for FAP-targeted cancer therapies.

Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis

“…To date only 2 studies have been published, where constitutive FAP knockout had a modest effect on bleomycin-induced pulmonary fibrosis progression 16 or on protection from the development of atherosclerosis. 44 However, constitutive FAP knockout cannot be compared with pharmacological inhibition with our highly specific FAPi. 45 , 46 , 47 Thus, Panaro et al 45 found that, although specific pharmacological FAP inhibition improved glucose tolerance in mice with diet induced obesity, FAP knockout did not protect these mice from insulin resistance, suggesting that elimination of FAP activity rather than constitutive genetic loss of FAP is essential for the beneficial effect.…”

The Role of Fibroblasts in Atherosclerosis Progression

“…Targeting proteins, expressed by activated fibroblasts could attenuate vascular inflammatory responses and ameliorate vascular disease, including atherosclerosis. Recently, it was discovered that inhibition of expression or activity of fibroblast activation protein (FAP), that is expressed in activated but not in quiescent fibroblasts and was found to be associated with atherosclerotic plaques, can attenuate progression of atherosclerosis by increasing plaque stability in experimental mice models of atherosclerosis [74]. The potential role of fibroblasts during atherosclerosis progression.…”

Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein

“…Cancer-associated fibroblasts (CAFs) are central components of the tumor microenvironment (TME) and play crucial roles in tumor development, immune suppression, and cancer invasion. − A notable biomarker highly expressed in CAFs is the fibroblast activation protein (FAP), a type II membrane-bound glycoprotein. FAP is upregulated in numerous epithelial carcinomas, wound healing, arthritis, atherosclerotic plaques, and fibrosis, with little expression in normal tissues. − Thus, it is considered a promising target for cancer diagnosis and therapy. − …”