Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction
Abstract Myocardial infarction (MI) is a lethal disease that causes irreversible cardiomyocyte death and subsequent cardiovascular remodeling. We have previously shown that the administration of recombinant progranulin (PGRN) protects against myocardial ischemia and reperfusion injury. However, the...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2023-00084 |
| _version_ | 1797666062015135744 |
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| author | Takahiro Sasaki Yoshiki Kuse Shinsuke Nakamura Masamitsu Shimazawa Hideaki Hara |
| author_facet | Takahiro Sasaki Yoshiki Kuse Shinsuke Nakamura Masamitsu Shimazawa Hideaki Hara |
| author_sort | Takahiro Sasaki |
| collection | DOAJ |
| description | Abstract Myocardial infarction (MI) is a lethal disease that causes irreversible cardiomyocyte death and subsequent cardiovascular remodeling. We have previously shown that the administration of recombinant progranulin (PGRN) protects against myocardial ischemia and reperfusion injury. However, the post‐MI role of PGRN remains unclear. In the present study, we investigated the effects of PGRN deficiency on cardiac remodeling after MI. Wild‐type and PGRN‐knockout mice were subjected to MI by ligation of the left coronary artery for histological, electrophysiological, and protein expression analysis. Cardiac macrophage subpopulations were analyzed by flow cytometry. Bone marrow‐derived macrophages (BMDMs) were acquired and treated with LPS + IFN‐γ and IL‐4 to evaluate mRNA levels and phagocytic ability. PGRN expression was gradually increased in the whole heart at 1, 3, and 7 days after MI. Macrophages abundantly expressed PGRN at the border areas at 3 days post‐MI. PGRN‐knockout mice showed higher mortality, increased LV fibrosis, and severe arrhythmia following MI. PGRN deficiency increased the levels of CD206 and MerTK expression and macrophage infiltration in the infarcted myocardium, which was attributed to a larger subpopulation of cardiac CCR2+ Ly6Clow CD11b+ macrophages. PGRN‐deficient BMDMs exhibited higher TGF‐β, IL‐4R, and lower IL‐1β, IL‐10 and increased acute phagocytosis following stimulation of LPS and IFN‐γ. PGRN deficiency reduced survival and increased cardiac fibrosis following MI with the induction of abnormal subpopulation of cardiac macrophages early after MI, thereby providing insight into the relationship between properly initiating cardiac repair and macrophage polarization after MI. |
| first_indexed | 2024-03-11T19:52:49Z |
| format | Article |
| id | doaj.art-e5899a43e4154047b0d500b993546eaf |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-03-11T19:52:49Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-e5899a43e4154047b0d500b993546eaf2023-10-05T04:41:03ZengWileyFASEB BioAdvances2573-98322023-10-0151039541110.1096/fba.2023-00084Progranulin deficiency exacerbates cardiac remodeling after myocardial infarctionTakahiro Sasaki0Yoshiki Kuse1Shinsuke Nakamura2Masamitsu Shimazawa3Hideaki Hara4Molecular Pharmacology, Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu JapanMolecular Pharmacology, Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu JapanMolecular Pharmacology, Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu JapanMolecular Pharmacology, Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu JapanMolecular Pharmacology, Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu JapanAbstract Myocardial infarction (MI) is a lethal disease that causes irreversible cardiomyocyte death and subsequent cardiovascular remodeling. We have previously shown that the administration of recombinant progranulin (PGRN) protects against myocardial ischemia and reperfusion injury. However, the post‐MI role of PGRN remains unclear. In the present study, we investigated the effects of PGRN deficiency on cardiac remodeling after MI. Wild‐type and PGRN‐knockout mice were subjected to MI by ligation of the left coronary artery for histological, electrophysiological, and protein expression analysis. Cardiac macrophage subpopulations were analyzed by flow cytometry. Bone marrow‐derived macrophages (BMDMs) were acquired and treated with LPS + IFN‐γ and IL‐4 to evaluate mRNA levels and phagocytic ability. PGRN expression was gradually increased in the whole heart at 1, 3, and 7 days after MI. Macrophages abundantly expressed PGRN at the border areas at 3 days post‐MI. PGRN‐knockout mice showed higher mortality, increased LV fibrosis, and severe arrhythmia following MI. PGRN deficiency increased the levels of CD206 and MerTK expression and macrophage infiltration in the infarcted myocardium, which was attributed to a larger subpopulation of cardiac CCR2+ Ly6Clow CD11b+ macrophages. PGRN‐deficient BMDMs exhibited higher TGF‐β, IL‐4R, and lower IL‐1β, IL‐10 and increased acute phagocytosis following stimulation of LPS and IFN‐γ. PGRN deficiency reduced survival and increased cardiac fibrosis following MI with the induction of abnormal subpopulation of cardiac macrophages early after MI, thereby providing insight into the relationship between properly initiating cardiac repair and macrophage polarization after MI.https://doi.org/10.1096/fba.2023-00084macrophagemyocardial infarctionprogranulin |
| spellingShingle | Takahiro Sasaki Yoshiki Kuse Shinsuke Nakamura Masamitsu Shimazawa Hideaki Hara Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction FASEB BioAdvances macrophage myocardial infarction progranulin |
| title | Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction |
| title_full | Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction |
| title_fullStr | Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction |
| title_full_unstemmed | Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction |
| title_short | Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction |
| title_sort | progranulin deficiency exacerbates cardiac remodeling after myocardial infarction |
| topic | macrophage myocardial infarction progranulin |
| url | https://doi.org/10.1096/fba.2023-00084 |
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