The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype
<b>Background:</b> Over the past few years, a better understanding of the biology of G-protein coupled receptors (GPRs) has led to the identification of several receptors as novel targets for free fatty acids (FFAs). FFAR4 has received special attention in the context of chronic inflamma...
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2021-09-01
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author | Anna Kiepura Kamila Stachyra Anna Wiśniewska Katarzyna Kuś Klaudia Czepiel Maciej Suski Magdalena Ulatowska-Białas Marcin Surmiak Rafał Olszanecki |
author_facet | Anna Kiepura Kamila Stachyra Anna Wiśniewska Katarzyna Kuś Klaudia Czepiel Maciej Suski Magdalena Ulatowska-Białas Marcin Surmiak Rafał Olszanecki |
author_sort | Anna Kiepura |
collection | DOAJ |
description | <b>Background:</b> Over the past few years, a better understanding of the biology of G-protein coupled receptors (GPRs) has led to the identification of several receptors as novel targets for free fatty acids (FFAs). FFAR4 has received special attention in the context of chronic inflammatory diseases, including atherosclerosis, obesity and NAFLD, through to its anti-inflammatory effect. <b>Methods:</b> The present study investigates the influence of prolonged treatment with TUG-891-FFAR4 agonist on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods. <b>Results:</b> TUG-891 administration has led to the reduction of atherosclerotic plaque size and necrotic cores in an apoE-knockout mice model. TUG-891-treated mice were administered subcutaneously at a dose of 20 mg/kg three times a week for 4 months. The FFAR4 agonist reduced the content of pro-inflammatory M1-like macrophages content in atherosclerotic plaques, as evidenced by immunohistochemical phenotyping and molecular methods. In atherosclerotic plaque, the population of smooth muscle cells increased as evidenced by α-SMA staining. We observed changes in G-CSF and eotaxin markers in the plasma of mice; changes in the levels of these markers in the blood may be related to macrophage differentiation. Importantly, we observed a significant increase in M2-like macrophage cells in atherosclerotic plaque and peritoneum. <b>Conclusions:</b> Prolonged administration of TUG-891 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR4 receptor holds promise for a new approach in the prevention or treatment of atherosclerosis. |
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spelling | doaj.art-9243426417d44adab542254a5d0e17e92023-11-22T13:27:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-012218977210.3390/ijms22189772The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 PhenotypeAnna Kiepura0Kamila Stachyra1Anna Wiśniewska2Katarzyna Kuś3Klaudia Czepiel4Maciej Suski5Magdalena Ulatowska-Białas6Marcin Surmiak7Rafał Olszanecki8Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, PolandChair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, PolandChair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, PolandChair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, PolandChair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, PolandChair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, PolandDepartment of Pathomorphology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, PolandDepartment of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, 8 Skawińska Street, 31-066 Kraków, PolandChair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland<b>Background:</b> Over the past few years, a better understanding of the biology of G-protein coupled receptors (GPRs) has led to the identification of several receptors as novel targets for free fatty acids (FFAs). FFAR4 has received special attention in the context of chronic inflammatory diseases, including atherosclerosis, obesity and NAFLD, through to its anti-inflammatory effect. <b>Methods:</b> The present study investigates the influence of prolonged treatment with TUG-891-FFAR4 agonist on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods. <b>Results:</b> TUG-891 administration has led to the reduction of atherosclerotic plaque size and necrotic cores in an apoE-knockout mice model. TUG-891-treated mice were administered subcutaneously at a dose of 20 mg/kg three times a week for 4 months. The FFAR4 agonist reduced the content of pro-inflammatory M1-like macrophages content in atherosclerotic plaques, as evidenced by immunohistochemical phenotyping and molecular methods. In atherosclerotic plaque, the population of smooth muscle cells increased as evidenced by α-SMA staining. We observed changes in G-CSF and eotaxin markers in the plasma of mice; changes in the levels of these markers in the blood may be related to macrophage differentiation. Importantly, we observed a significant increase in M2-like macrophage cells in atherosclerotic plaque and peritoneum. <b>Conclusions:</b> Prolonged administration of TUG-891 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR4 receptor holds promise for a new approach in the prevention or treatment of atherosclerosis.https://www.mdpi.com/1422-0067/22/18/9772free fatty acid receptorsFFAR4inflammationatherosclerosisapoE-knockout micemacrophages |
spellingShingle | Anna Kiepura Kamila Stachyra Anna Wiśniewska Katarzyna Kuś Klaudia Czepiel Maciej Suski Magdalena Ulatowska-Białas Marcin Surmiak Rafał Olszanecki The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype International Journal of Molecular Sciences free fatty acid receptors FFAR4 inflammation atherosclerosis apoE-knockout mice macrophages |
title | The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype |
title_full | The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype |
title_fullStr | The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype |
title_full_unstemmed | The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype |
title_short | The Anti-Atherosclerotic Action of FFAR4 Agonist TUG-891 in ApoE–Knockout Mice Is Associated with Increased Macrophage Polarization towards M2 Phenotype |
title_sort | anti atherosclerotic action of ffar4 agonist tug 891 in apoe knockout mice is associated with increased macrophage polarization towards m2 phenotype |
topic | free fatty acid receptors FFAR4 inflammation atherosclerosis apoE-knockout mice macrophages |
url | https://www.mdpi.com/1422-0067/22/18/9772 |
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