Journal article
Deletion of fibroblast activation protein provides atheroprotection.
- Stein S Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Weber J Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Nusser-Stein S Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Pahla J Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Zhang HE Centenary Institute, The University of Sydney, Faculty of Medicine and Health, Sydney NSW, Australia.
- Mohammed SA Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Oppi S Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Gaul DS Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Paneni F Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Tailleux A University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Lille, France.
- Staels B University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, Lille, France.
- von Meyenn F Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
- Ruschitzka F Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, CH-8091 Zurich Switzerland.
- Gorrell MD Centenary Institute, The University of Sydney, Faculty of Medicine and Health, Sydney NSW, Australia.
- Lüscher TF Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- Matter CM Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.
- 2020-05-14
Published in:
- Cardiovascular research. - 2020
English
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 (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.
- Language
-
- English
- Open access status
- closed
- Identifiers
-
- DOI 10.1093/cvr/cvaa142
- PMID 32402085
- Persistent URL
- https://sonar.ch/global/documents/178962
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