FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation
Abstract Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains u...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-04-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06646-1 |
| _version_ | 1797208977512071168 |
|---|---|
| author | Ya Li Caojian Zuo Xiaoyu Wu Yu Ding Yong Wei Songwen Chen Xiaofeng Lu Juan Xu Shaowen Liu Genqing Zhou Lidong Cai |
| author_facet | Ya Li Caojian Zuo Xiaoyu Wu Yu Ding Yong Wei Songwen Chen Xiaofeng Lu Juan Xu Shaowen Liu Genqing Zhou Lidong Cai |
| author_sort | Ya Li |
| collection | DOAJ |
| description | Abstract Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains unknown. FBXL8 was primarily expressed in cardiac fibroblasts (CFs) and remarkably decreased in CFs treated by TGFβ and heart subjected to MI. The echocardiography and histology data suggested that adeno-associated viruses (AAV9)-mediated FBXL8 overexpression had improved cardiac function and ameliorated post-MI cardiac fibrosis. In vitro, FBXL8 overexpression prevented TGFβ-induced proliferation, migration, contraction, and collagen secretion in CFs, while knockdown of FBXL8 demonstrated opposite effects. Mechanistically, FBXL8 interacted with Snail1 to promote Snail1 degradation through the ubiquitin–proteasome system and decreased the activation of RhoA. Moreover, the FBXL8ΔC3 binding domain was indispensable for Snail1 interaction and degradation. Ectopic Snail1 expression partly abolished the effects mediated by FBXL8 overexpression in CFs treated by TGFβ. These results characterized the role of FBXL8 in regulating the ubiquitin-mediated degradation of Snail1 and revealed the underlying molecular mechanism of how MI up-regulated the myofibroblasts differentiation-inducer Snail1 and suggested that FBXL8 may be a potential curative target for improving post-MI cardiac function. |
| first_indexed | 2024-04-24T09:47:23Z |
| format | Article |
| id | doaj.art-291dcdb8259244b1b39c8726b5fbc0e2 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-24T09:47:23Z |
| publishDate | 2024-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-291dcdb8259244b1b39c8726b5fbc0e22024-04-14T11:30:50ZengNature Publishing GroupCell Death and Disease2041-48892024-04-0115411310.1038/s41419-024-06646-1FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradationYa Li0Caojian Zuo1Xiaoyu Wu2Yu Ding3Yong Wei4Songwen Chen5Xiaofeng Lu6Juan Xu7Shaowen Liu8Genqing Zhou9Lidong Cai10Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Key Laboratory, Lianshui County People’s Hospital, Kangda College of Nanjing Medical UniversityDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineAbstract Abnormal cardiac fibrosis is the main pathological change of post-myocardial infarction (MI) heart failure. Although the E3 ubiquitin ligase FBXL8 is a key regulator in the cell cycle, cell proliferation, and inflammation, its role in post-MI ventricular fibrosis and heart failure remains unknown. FBXL8 was primarily expressed in cardiac fibroblasts (CFs) and remarkably decreased in CFs treated by TGFβ and heart subjected to MI. The echocardiography and histology data suggested that adeno-associated viruses (AAV9)-mediated FBXL8 overexpression had improved cardiac function and ameliorated post-MI cardiac fibrosis. In vitro, FBXL8 overexpression prevented TGFβ-induced proliferation, migration, contraction, and collagen secretion in CFs, while knockdown of FBXL8 demonstrated opposite effects. Mechanistically, FBXL8 interacted with Snail1 to promote Snail1 degradation through the ubiquitin–proteasome system and decreased the activation of RhoA. Moreover, the FBXL8ΔC3 binding domain was indispensable for Snail1 interaction and degradation. Ectopic Snail1 expression partly abolished the effects mediated by FBXL8 overexpression in CFs treated by TGFβ. These results characterized the role of FBXL8 in regulating the ubiquitin-mediated degradation of Snail1 and revealed the underlying molecular mechanism of how MI up-regulated the myofibroblasts differentiation-inducer Snail1 and suggested that FBXL8 may be a potential curative target for improving post-MI cardiac function.https://doi.org/10.1038/s41419-024-06646-1 |
| spellingShingle | Ya Li Caojian Zuo Xiaoyu Wu Yu Ding Yong Wei Songwen Chen Xiaofeng Lu Juan Xu Shaowen Liu Genqing Zhou Lidong Cai FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation Cell Death and Disease |
| title | FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation |
| title_full | FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation |
| title_fullStr | FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation |
| title_full_unstemmed | FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation |
| title_short | FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation |
| title_sort | fbxl8 inhibits post myocardial infarction cardiac fibrosis by targeting snail1 for ubiquitin proteasome degradation |
| url | https://doi.org/10.1038/s41419-024-06646-1 |
| work_keys_str_mv | AT yali fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT caojianzuo fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT xiaoyuwu fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT yuding fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT yongwei fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT songwenchen fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT xiaofenglu fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT juanxu fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT shaowenliu fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT genqingzhou fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation AT lidongcai fbxl8inhibitspostmyocardialinfarctioncardiacfibrosisbytargetingsnail1forubiquitinproteasomedegradation |