SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation
Abstract The macrophage-associated inflammation response plays an important role in myocardial ischemia-reperfusion injury (MIRI). SHEP1(SH2 domain-containing Eph receptor-binding protein 1) has been implicated in adhesion and migration of inflammatory cells. However, the role and molecular mechanis...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07282-5 |
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| author | Tingwen Gao Zhenyang Guo Xinyu Weng Yikai Cui Peng Li Tao Hu Wei Luo Zheng Dong Peng Wei Yun Cai Yijing Lu Rifeng Gao Hua Li Xin Zhong Junbo Ge |
| author_facet | Tingwen Gao Zhenyang Guo Xinyu Weng Yikai Cui Peng Li Tao Hu Wei Luo Zheng Dong Peng Wei Yun Cai Yijing Lu Rifeng Gao Hua Li Xin Zhong Junbo Ge |
| author_sort | Tingwen Gao |
| collection | DOAJ |
| description | Abstract The macrophage-associated inflammation response plays an important role in myocardial ischemia-reperfusion injury (MIRI). SHEP1(SH2 domain-containing Eph receptor-binding protein 1) has been implicated in adhesion and migration of inflammatory cells. However, the role and molecular mechanism of SHEP1 regulating macrophage remains unclear during MIRI. Here, the expression of SHEP1 was increased in macrophages co-cultured with hypoxia-reoxygenated cardiomyocytes and within ischemia-reperfusion injured myocardium at the early stage of injury. Cell migration and inflammation were also enhanced in SHEP1 knock-out macrophages and macrophage-specific deficiency of SHEP1 mice under MIRI, which further led to deteriorated cardiac injury and cardiac function in vivo. Mechanistically, macrophage-derived SHEP1 competitively bound to G3BP1 to suppress inflammation via the MAPK pathway. In addition, administrating inhibitor of G3BP1 could improve cardiac function in macrophage-specific deficiency of SHEP1 mice under MIRI. Our results demonstrate that SHEP1 deficiency in macrophages exacerbates MIRI through G3BP1-dependent signaling pathway. SHEP1-G3BP1 interaction are therefore indispensable for SHEP1 regulated- infiltration and proinflammatory responses of macrophages, which provided a potential and clinically significant therapeutic target for MIRI. |
| format | Article |
| id | doaj-art-0aea229ba4bd4aeeb14471269ec6972b |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-0aea229ba4bd4aeeb14471269ec6972b2024-12-22T12:51:04ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211310.1038/s41419-024-07282-5SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammationTingwen Gao0Zhenyang Guo1Xinyu Weng2Yikai Cui3Peng Li4Tao Hu5Wei Luo6Zheng Dong7Peng Wei8Yun Cai9Yijing Lu10Rifeng Gao11Hua Li12Xin Zhong13Junbo Ge14Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Xijing Hospital, Fourth Military Medical UniversityDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Shanghai Jiao Tong University Affliated Sixth People’s HospitalDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesDepartment of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular DiseasesAbstract The macrophage-associated inflammation response plays an important role in myocardial ischemia-reperfusion injury (MIRI). SHEP1(SH2 domain-containing Eph receptor-binding protein 1) has been implicated in adhesion and migration of inflammatory cells. However, the role and molecular mechanism of SHEP1 regulating macrophage remains unclear during MIRI. Here, the expression of SHEP1 was increased in macrophages co-cultured with hypoxia-reoxygenated cardiomyocytes and within ischemia-reperfusion injured myocardium at the early stage of injury. Cell migration and inflammation were also enhanced in SHEP1 knock-out macrophages and macrophage-specific deficiency of SHEP1 mice under MIRI, which further led to deteriorated cardiac injury and cardiac function in vivo. Mechanistically, macrophage-derived SHEP1 competitively bound to G3BP1 to suppress inflammation via the MAPK pathway. In addition, administrating inhibitor of G3BP1 could improve cardiac function in macrophage-specific deficiency of SHEP1 mice under MIRI. Our results demonstrate that SHEP1 deficiency in macrophages exacerbates MIRI through G3BP1-dependent signaling pathway. SHEP1-G3BP1 interaction are therefore indispensable for SHEP1 regulated- infiltration and proinflammatory responses of macrophages, which provided a potential and clinically significant therapeutic target for MIRI.https://doi.org/10.1038/s41419-024-07282-5 |
| spellingShingle | Tingwen Gao Zhenyang Guo Xinyu Weng Yikai Cui Peng Li Tao Hu Wei Luo Zheng Dong Peng Wei Yun Cai Yijing Lu Rifeng Gao Hua Li Xin Zhong Junbo Ge SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation Cell Death and Disease |
| title | SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation |
| title_full | SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation |
| title_fullStr | SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation |
| title_full_unstemmed | SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation |
| title_short | SHEP1 alleviates cardiac ischemia reperfusion injury via targeting G3BP1 to regulate macrophage infiltration and inflammation |
| title_sort | shep1 alleviates cardiac ischemia reperfusion injury via targeting g3bp1 to regulate macrophage infiltration and inflammation |
| url | https://doi.org/10.1038/s41419-024-07282-5 |
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