Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype
Abstract Fibrotic remodeling is an adverse consequence of immune response-driven phenotypic modulation of cardiac cells following myocardial infarction (MI). MicroRNA-146b (miR-146b) is an active regulator of immunomodulation, but its function in the cardiac inflammatory cascade and its clinical imp...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2020-08-01
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| Series: | Protein & Cell |
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| Online Access: | https://doi.org/10.1007/s13238-020-00750-6 |
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| author | Yiteng Liao Hao Li Hao Cao Yun Dong Lei Gao Zhongmin Liu Junbo Ge Hongming Zhu |
| author_facet | Yiteng Liao Hao Li Hao Cao Yun Dong Lei Gao Zhongmin Liu Junbo Ge Hongming Zhu |
| author_sort | Yiteng Liao |
| collection | DOAJ |
| description | Abstract Fibrotic remodeling is an adverse consequence of immune response-driven phenotypic modulation of cardiac cells following myocardial infarction (MI). MicroRNA-146b (miR-146b) is an active regulator of immunomodulation, but its function in the cardiac inflammatory cascade and its clinical implication in fibrotic remodeling following MI remain largely unknown. Herein, miR-146b-5p was found to be upregulated in the infarcted myocardium of mice and the serum of myocardial ischemia patients. Gain- and loss-of-function experiments demonstrated that miR-146b-5p was a hypoxia-induced regulator that governed the pro-fibrotic phenotype transition of cardiac cells. Overexpression of miR-146b-5p activated fibroblast proliferation, migration, and fibroblast-to-myofibroblast transition, impaired endothelial cell function and stress survival, and disturbed macrophage paracrine signaling. Interestingly, the opposite effects were observed when miR-146b-5p expression was inhibited. Luciferase assays and rescue studies demonstrated that the miR-146b-5p target genes mediating the above phenotypic modulations included interleukin 1 receptor associated kinase 1 (IRAK1) and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). Local delivery of a miR-146b-5p antagomir significantly reduced fibrosis and cell death, and upregulated capillary and reparative macrophages in the infarcted myocardium to restore cardiac remodeling and function in both mouse and porcine MI models. Local inhibition of miR-146b-5p may represent a novel therapeutic approach to treat cardiac fibrotic remodeling and dysfunction following MI. |
| first_indexed | 2024-03-12T19:43:32Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T19:43:32Z |
| publishDate | 2020-08-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-b64520b10dfb4f448c84278a583cf6542023-08-02T03:40:45ZengOxford University PressProtein & Cell1674-800X1674-80182020-08-0112319421210.1007/s13238-020-00750-6Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotypeYiteng Liao0Hao Li1Hao Cao2Yun Dong3Lei Gao4Zhongmin Liu5Junbo Ge6Hongming Zhu7Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of MedicineResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of MedicineDepartment of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of MedicineDepartment of Ultrasound in Medicine, Shanghai East Hospital, Tongji University School of MedicineResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of MedicineResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of MedicineDepartment of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital of Fudan UniversityResearch Center for Translational Medicine, Shanghai East Hospital, Tongji University School of MedicineAbstract Fibrotic remodeling is an adverse consequence of immune response-driven phenotypic modulation of cardiac cells following myocardial infarction (MI). MicroRNA-146b (miR-146b) is an active regulator of immunomodulation, but its function in the cardiac inflammatory cascade and its clinical implication in fibrotic remodeling following MI remain largely unknown. Herein, miR-146b-5p was found to be upregulated in the infarcted myocardium of mice and the serum of myocardial ischemia patients. Gain- and loss-of-function experiments demonstrated that miR-146b-5p was a hypoxia-induced regulator that governed the pro-fibrotic phenotype transition of cardiac cells. Overexpression of miR-146b-5p activated fibroblast proliferation, migration, and fibroblast-to-myofibroblast transition, impaired endothelial cell function and stress survival, and disturbed macrophage paracrine signaling. Interestingly, the opposite effects were observed when miR-146b-5p expression was inhibited. Luciferase assays and rescue studies demonstrated that the miR-146b-5p target genes mediating the above phenotypic modulations included interleukin 1 receptor associated kinase 1 (IRAK1) and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). Local delivery of a miR-146b-5p antagomir significantly reduced fibrosis and cell death, and upregulated capillary and reparative macrophages in the infarcted myocardium to restore cardiac remodeling and function in both mouse and porcine MI models. Local inhibition of miR-146b-5p may represent a novel therapeutic approach to treat cardiac fibrotic remodeling and dysfunction following MI.https://doi.org/10.1007/s13238-020-00750-6cardiac fibrosismicroRNAporcine modelmyocardial infarction |
| spellingShingle | Yiteng Liao Hao Li Hao Cao Yun Dong Lei Gao Zhongmin Liu Junbo Ge Hongming Zhu Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype Protein & Cell cardiac fibrosis microRNA porcine model myocardial infarction |
| title | Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype |
| title_full | Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype |
| title_fullStr | Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype |
| title_full_unstemmed | Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype |
| title_short | Therapeutic silencing miR-146b-5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype |
| title_sort | therapeutic silencing mir 146b 5p improves cardiac remodeling in a porcine model of myocardial infarction by modulating the wound reparative phenotype |
| topic | cardiac fibrosis microRNA porcine model myocardial infarction |
| url | https://doi.org/10.1007/s13238-020-00750-6 |
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