ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3
Abstract Mitochondrial dysfunction is a key factor in exacerbating pressure overload‐induced cardiac hypertrophy and is linked to increased morbidity and mortality. ECSIT, a crucial adaptor for inflammation and mitochondrial function, has been reported to express multiple transcripts in various spec...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202414358 |
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| author | Xia Lu Tingting Tong Haoliang Sun Yi Chen Yongfeng Shao Pengxi Shi Linli Que Li Liu Guoqing Zhu Qi Chen Chuanfu Li Jiantao Li Shuo Yang Yuehua Li |
| author_facet | Xia Lu Tingting Tong Haoliang Sun Yi Chen Yongfeng Shao Pengxi Shi Linli Que Li Liu Guoqing Zhu Qi Chen Chuanfu Li Jiantao Li Shuo Yang Yuehua Li |
| author_sort | Xia Lu |
| collection | DOAJ |
| description | Abstract Mitochondrial dysfunction is a key factor in exacerbating pressure overload‐induced cardiac hypertrophy and is linked to increased morbidity and mortality. ECSIT, a crucial adaptor for inflammation and mitochondrial function, has been reported to express multiple transcripts in various species and tissues, leading to distinct protein isoforms with diverse subcellular localizations and functions. However, whether an unknown ECSIT isoform exists in cardiac cells and its potential role in regulating mitochondrial function and pathological cardiac hypertrophy has remained unclear. This study identified a 42‐kDa ECSIT isoform encoded by the transcript variant Ecsit‐X4, which is highly expressed in the mitochondria of adult cardiomyocytes but down‐regulated in hypertrophic human heart samples and TAC‐treated mouse hearts. AAV9‐mediated Ecsit‐X4 gene therapy, administered either before or after TAC surgery, significantly attenuated cardiac hypertrophy. Cardiomyocyte‐specific Ecsit deficiency worsened TAC‐induced cardiac hypertrophy, while Ecsit‐X4 compensation independently rescued hypertrophic phenotypes in EcsitcKO mice. Mechanistically, ECSIT‐X4 localized to the mitochondria and interacted with STAT3, leading to increased STAT3 levels and enhanced serine 727 phosphorylation in cardiomyocyte mitochondria, thereby promoting strong mitochondrial bioenergetics. This study identified a novel transcript variant of ECSIT localized in the mitochondria of adult cardiomyocytes and highlights its potential as a therapeutic target for heart failure. |
| format | Article |
| id | doaj-art-c34ac66ea54341bfa3c98ef5e463fe34 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-c34ac66ea54341bfa3c98ef5e463fe342025-08-20T01:51:48ZengWileyAdvanced Science2198-38442025-02-01128n/an/a10.1002/advs.202414358ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3Xia Lu0Tingting Tong1Haoliang Sun2Yi Chen3Yongfeng Shao4Pengxi Shi5Linli Que6Li Liu7Guoqing Zhu8Qi Chen9Chuanfu Li10Jiantao Li11Shuo Yang12Yuehua Li13Key Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaDepartment of Cardiovascular Surgery The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu 210029 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaDepartment of Cardiovascular Surgery The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu 210029 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaDepartment of Geriatrics the First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu 210029 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaDepartment of Surgery East Tennessee State University Campus Box 70575 Johnson City TN 37614‐0575 USAKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaDepartment of Immunology Key Laboratory of Immunological Environment and Disease State Key Laboratory of Reproductive Medicine Nanjing Medical University Nanjing Jiangsu 211166 ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational Medicine School of Basic Medical Sciences Nanjing Medical University Nanjing Jiangsu 211166 ChinaAbstract Mitochondrial dysfunction is a key factor in exacerbating pressure overload‐induced cardiac hypertrophy and is linked to increased morbidity and mortality. ECSIT, a crucial adaptor for inflammation and mitochondrial function, has been reported to express multiple transcripts in various species and tissues, leading to distinct protein isoforms with diverse subcellular localizations and functions. However, whether an unknown ECSIT isoform exists in cardiac cells and its potential role in regulating mitochondrial function and pathological cardiac hypertrophy has remained unclear. This study identified a 42‐kDa ECSIT isoform encoded by the transcript variant Ecsit‐X4, which is highly expressed in the mitochondria of adult cardiomyocytes but down‐regulated in hypertrophic human heart samples and TAC‐treated mouse hearts. AAV9‐mediated Ecsit‐X4 gene therapy, administered either before or after TAC surgery, significantly attenuated cardiac hypertrophy. Cardiomyocyte‐specific Ecsit deficiency worsened TAC‐induced cardiac hypertrophy, while Ecsit‐X4 compensation independently rescued hypertrophic phenotypes in EcsitcKO mice. Mechanistically, ECSIT‐X4 localized to the mitochondria and interacted with STAT3, leading to increased STAT3 levels and enhanced serine 727 phosphorylation in cardiomyocyte mitochondria, thereby promoting strong mitochondrial bioenergetics. This study identified a novel transcript variant of ECSIT localized in the mitochondria of adult cardiomyocytes and highlights its potential as a therapeutic target for heart failure.https://doi.org/10.1002/advs.202414358cardiac hypertrophyECSIT‐X4mitochondriaSTAT3 |
| spellingShingle | Xia Lu Tingting Tong Haoliang Sun Yi Chen Yongfeng Shao Pengxi Shi Linli Que Li Liu Guoqing Zhu Qi Chen Chuanfu Li Jiantao Li Shuo Yang Yuehua Li ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3 Advanced Science cardiac hypertrophy ECSIT‐X4 mitochondria STAT3 |
| title | ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3 |
| title_full | ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3 |
| title_fullStr | ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3 |
| title_full_unstemmed | ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3 |
| title_short | ECSIT‐X4 is Required for Preventing Pressure Overload‐Induced Cardiac Hypertrophy via Regulating Mitochondrial STAT3 |
| title_sort | ecsit x4 is required for preventing pressure overload induced cardiac hypertrophy via regulating mitochondrial stat3 |
| topic | cardiac hypertrophy ECSIT‐X4 mitochondria STAT3 |
| url | https://doi.org/10.1002/advs.202414358 |
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