Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial Region
The study of the mechanisms of development and progression of fibrosis is one of the key directions of modern cardiology. Our work suggests that the urokinase receptor (uPAR) is involved in the regulation of mesothelial cell activity and epicardial fibrosis development, which, when interacting with...
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Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russia
2021-12-01
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| Series: | Общая реаниматология |
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| Online Access: | https://www.reanimatology.com/rmt/article/view/2159 |
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| author | K. V. Dergilev Z. I. Tsokolayeva I. B. Beloglazova Yu. D. Vasilets D. O. Traktuyev B. N. Kulbitsky E. V. Parfenova |
| author_facet | K. V. Dergilev Z. I. Tsokolayeva I. B. Beloglazova Yu. D. Vasilets D. O. Traktuyev B. N. Kulbitsky E. V. Parfenova |
| author_sort | K. V. Dergilev |
| collection | DOAJ |
| description | The study of the mechanisms of development and progression of fibrosis is one of the key directions of modern cardiology. Our work suggests that the urokinase receptor (uPAR) is involved in the regulation of mesothelial cell activity and epicardial fibrosis development, which, when interacting with specific ligands and intermediate proteins, can activate intracellular signaling, trigger the cascade of proteolytic reactions, including local plasmin formation and activation of matrix metalloproteinases, providing matrix remodeling.Objective: to perform a comparative study of fibrogenic activity of the epicardium in the hearts of uPAR-/- and wild-type animals and evaluate the effect of cardiac microenvironment factors on the migration activity of epicardial mesothelial cells.Material and methods. We used histological and immunofluorescent staining, microarray analysis of proinflammatory cytokine levels, and a method for assessing the migratory properties of epicardial cells.Results. Results. We found that compared to wild-type animals, uPAR-/- animals show significant thickening of the epicardial area (2.46+0.77 (uPAR-/- mice) and 1.02+0.17 (Wt mice) relative units, P=0.033) accompanied by accumulation of extracellular matrix proteins. Deficiency of uPAR gene leads to formation of proinflammatory microenvironment in the heart (increased levels of proinflammatory factors such as IL-1, IL-13, IL-17, RANTES and MIP1), increased migratory activity of epicardial mesothelial cells, accumulation of TCF21+fibroblast/myofibroblast precursors (29.8+13.7 (uPAR-/- mouse) and 3.03+0.8 (Wt mouse) cells per visual field,P=0.02), as well as development of subepicardial fibrosis.Conclusion. These findings suggest that uPAR is a promising candidate for the developing targeted agents to prevent the development and progression of cardiac fibrosis. |
| format | Article |
| id | doaj-art-e6564e0e41bf4af2af7b2ef37346cd1e |
| institution | Kabale University |
| issn | 1813-9779 2411-7110 |
| language | English |
| publishDate | 2021-12-01 |
| publisher | Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russia |
| record_format | Article |
| series | Общая реаниматология |
| spelling | doaj-art-e6564e0e41bf4af2af7b2ef37346cd1e2025-08-20T03:35:08ZengFederal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, RussiaОбщая реаниматология1813-97792411-71102021-12-01176495510.15360/1813-9779-2021-6-49-551827Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial RegionK. V. Dergilev0Z. I. Tsokolayeva1I. B. Beloglazova2Yu. D. Vasilets3D. O. Traktuyev4B. N. Kulbitsky5E. V. Parfenova6Angiogenesis Laboratory, Experimental Cardiology Institute, National Medical Research Center for Cardiology, Ministry of Health of RussiaAngiogenesis Laboratory, Experimental Cardiology Institute, National Medical Research Center for Cardiology, Ministry of Health of Russia; V. A. Negovsky Research Institute of General Reanimatology, Federal Research and Clinical Center of Intensive Care Medicine and RehabilitologyAngiogenesis Laboratory, Experimental Cardiology Institute, National Medical Research Center for Cardiology, Ministry of Health of RussiaAngiogenesis Laboratory, Experimental Cardiology Institute, National Medical Research Center for Cardiology, Ministry of Health of RussiaCenter for Regenerative Medicine, Department of Medicine, College of Medicine, University of FloridaPathology of Terminal States Section, Forensic Medicine Department, Research Institute of Human Morphology; Forensic Medicine Department, Peoples’ Friendship University of RussiaAngiogenesis Laboratory, Experimental Cardiology Institute, National Medical Research Center for Cardiology, Ministry of Health of Russia; Laboratory of Postgenomic Technologies in Medicine, Fundamental Medicine Faculty, Lomonosov Moscow State UniversityThe study of the mechanisms of development and progression of fibrosis is one of the key directions of modern cardiology. Our work suggests that the urokinase receptor (uPAR) is involved in the regulation of mesothelial cell activity and epicardial fibrosis development, which, when interacting with specific ligands and intermediate proteins, can activate intracellular signaling, trigger the cascade of proteolytic reactions, including local plasmin formation and activation of matrix metalloproteinases, providing matrix remodeling.Objective: to perform a comparative study of fibrogenic activity of the epicardium in the hearts of uPAR-/- and wild-type animals and evaluate the effect of cardiac microenvironment factors on the migration activity of epicardial mesothelial cells.Material and methods. We used histological and immunofluorescent staining, microarray analysis of proinflammatory cytokine levels, and a method for assessing the migratory properties of epicardial cells.Results. Results. We found that compared to wild-type animals, uPAR-/- animals show significant thickening of the epicardial area (2.46+0.77 (uPAR-/- mice) and 1.02+0.17 (Wt mice) relative units, P=0.033) accompanied by accumulation of extracellular matrix proteins. Deficiency of uPAR gene leads to formation of proinflammatory microenvironment in the heart (increased levels of proinflammatory factors such as IL-1, IL-13, IL-17, RANTES and MIP1), increased migratory activity of epicardial mesothelial cells, accumulation of TCF21+fibroblast/myofibroblast precursors (29.8+13.7 (uPAR-/- mouse) and 3.03+0.8 (Wt mouse) cells per visual field,P=0.02), as well as development of subepicardial fibrosis.Conclusion. These findings suggest that uPAR is a promising candidate for the developing targeted agents to prevent the development and progression of cardiac fibrosis.https://www.reanimatology.com/rmt/article/view/2159fibrosisepicardial mesotheliumurokinase receptor |
| spellingShingle | K. V. Dergilev Z. I. Tsokolayeva I. B. Beloglazova Yu. D. Vasilets D. O. Traktuyev B. N. Kulbitsky E. V. Parfenova Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial Region Общая реаниматология fibrosis epicardial mesothelium urokinase receptor |
| title | Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial Region |
| title_full | Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial Region |
| title_fullStr | Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial Region |
| title_full_unstemmed | Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial Region |
| title_short | Involvement of Urokinase-Type Plasminogen Activator Receptor in the Formation of a Profibrotic Microenvironment in the Epicardial Region |
| title_sort | involvement of urokinase type plasminogen activator receptor in the formation of a profibrotic microenvironment in the epicardial region |
| topic | fibrosis epicardial mesothelium urokinase receptor |
| url | https://www.reanimatology.com/rmt/article/view/2159 |
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