Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis
Aortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfuncti...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-07-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/15/8439 |
| _version_ | 1797441889672101888 |
|---|---|
| author | Mattie Garaikoetxea Ernesto Martín-Núñez Adela Navarro Lara Matilla Amaya Fernández-Celis Vanessa Arrieta Amaia García-Peña Alicia Gainza Virginia Álvarez Rafael Sádaba Eva Jover Natalia López-Andrés |
| author_facet | Mattie Garaikoetxea Ernesto Martín-Núñez Adela Navarro Lara Matilla Amaya Fernández-Celis Vanessa Arrieta Amaia García-Peña Alicia Gainza Virginia Álvarez Rafael Sádaba Eva Jover Natalia López-Andrés |
| author_sort | Mattie Garaikoetxea |
| collection | DOAJ |
| description | Aortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfunction, and plaque vulnerability. FABP4 pharmacological blockade has been shown to be effective for the treatment of atherosclerosis by modulating metabolic and inflammatory pathways. We aimed to analyze the sex-specific expression of FABP4 in AS and its potential role as a therapeutic target. A total of 226 patients (61.5% men) with severe AS undergoing surgical AV replacement were recruited. The FABP4 levels were increased in the AVs of AS patients compared to the control subjects, showing greater expression in the fibrocalcific regions. Male AVs exhibited higher levels of FABP4 compared to females, correlating with markers of inflammation (IL-6, Rantes), apoptosis (Bax, caspase-3, Bcl-2), and calcification (IL-8, BMP-2 and BMP-4). VICs derived from AS patients showed the basal expression of FABP4 in vitro. Osteogenic media induced upregulation of intracellular and secreted FABP4 levels in male VICs after 7 days, along with increased levels of inflammatory, pro-apoptotic, and osteogenic markers. Treatment with BMS309403, a specific inhibitor of FABP4, prevented from all of these changes. Thus, we propose FABP4 as a new sex-specific pharmacological therapeutic target in AS. |
| first_indexed | 2024-03-09T12:32:44Z |
| format | Article |
| id | doaj.art-452bd79e33294ebca5c4518dd315382e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:32:44Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-452bd79e33294ebca5c4518dd315382e2023-11-30T22:28:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012315843910.3390/ijms23158439Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic StenosisMattie Garaikoetxea0Ernesto Martín-Núñez1Adela Navarro2Lara Matilla3Amaya Fernández-Celis4Vanessa Arrieta5Amaia García-Peña6Alicia Gainza7Virginia Álvarez8Rafael Sádaba9Eva Jover10Natalia López-Andrés11Cardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainCardiovascular Translational Research, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdISNA, 31008 Pamplona, SpainAortic stenosis (AS) is a fibrocalcific disease of the aortic valves (AVs). Sex-differences in AS pathophysiology have recently been described. High levels of fatty acid-binding protein 4 (FAPB4) in atherosclerotic plaques have been associated with increased local inflammation, endothelial dysfunction, and plaque vulnerability. FABP4 pharmacological blockade has been shown to be effective for the treatment of atherosclerosis by modulating metabolic and inflammatory pathways. We aimed to analyze the sex-specific expression of FABP4 in AS and its potential role as a therapeutic target. A total of 226 patients (61.5% men) with severe AS undergoing surgical AV replacement were recruited. The FABP4 levels were increased in the AVs of AS patients compared to the control subjects, showing greater expression in the fibrocalcific regions. Male AVs exhibited higher levels of FABP4 compared to females, correlating with markers of inflammation (IL-6, Rantes), apoptosis (Bax, caspase-3, Bcl-2), and calcification (IL-8, BMP-2 and BMP-4). VICs derived from AS patients showed the basal expression of FABP4 in vitro. Osteogenic media induced upregulation of intracellular and secreted FABP4 levels in male VICs after 7 days, along with increased levels of inflammatory, pro-apoptotic, and osteogenic markers. Treatment with BMS309403, a specific inhibitor of FABP4, prevented from all of these changes. Thus, we propose FABP4 as a new sex-specific pharmacological therapeutic target in AS.https://www.mdpi.com/1422-0067/23/15/8439FABP4aortic stenosissexual dimorphisminflammationapoptosiscalcification |
| spellingShingle | Mattie Garaikoetxea Ernesto Martín-Núñez Adela Navarro Lara Matilla Amaya Fernández-Celis Vanessa Arrieta Amaia García-Peña Alicia Gainza Virginia Álvarez Rafael Sádaba Eva Jover Natalia López-Andrés Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis International Journal of Molecular Sciences FABP4 aortic stenosis sexual dimorphism inflammation apoptosis calcification |
| title | Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis |
| title_full | Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis |
| title_fullStr | Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis |
| title_full_unstemmed | Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis |
| title_short | Targeting Fatty Acid-Binding Protein 4 Improves Pathologic Features of Aortic Stenosis |
| title_sort | targeting fatty acid binding protein 4 improves pathologic features of aortic stenosis |
| topic | FABP4 aortic stenosis sexual dimorphism inflammation apoptosis calcification |
| url | https://www.mdpi.com/1422-0067/23/15/8439 |
| work_keys_str_mv | AT mattiegaraikoetxea targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT ernestomartinnunez targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT adelanavarro targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT laramatilla targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT amayafernandezcelis targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT vanessaarrieta targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT amaiagarciapena targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT aliciagainza targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT virginiaalvarez targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT rafaelsadaba targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT evajover targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis AT natalialopezandres targetingfattyacidbindingprotein4improvespathologicfeaturesofaorticstenosis |