Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation
Doxorubicin (DOX) is a prevalent chemotherapeutic drug for treating several malignancies. However, the mechanisms of DOX induced cardiac toxicity is not fully understood. Previous studies have demonstrated that autophagy activation is essential in DOX-induced cardiac toxicity. Nevertheless, studies...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-01-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1496380/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832584360689139712 |
|---|---|
| author | Ai-Li Xu Zheng Shen Shi-Hao Wang Hai-Yun Luan Yong Xu Ze-Chun Kang Zi-Qi Liao Jie Liu Xiao-Lei Duan Wei-Hua Bian Hui Sun Xin Xie |
| author_facet | Ai-Li Xu Zheng Shen Shi-Hao Wang Hai-Yun Luan Yong Xu Ze-Chun Kang Zi-Qi Liao Jie Liu Xiao-Lei Duan Wei-Hua Bian Hui Sun Xin Xie |
| author_sort | Ai-Li Xu |
| collection | DOAJ |
| description | Doxorubicin (DOX) is a prevalent chemotherapeutic drug for treating several malignancies. However, the mechanisms of DOX induced cardiac toxicity is not fully understood. Previous studies have demonstrated that autophagy activation is essential in DOX-induced cardiac toxicity. Nevertheless, studies on the role of autophagy protein 5 (ATG5) in DOX-induced cardiac toxicity remain limited. Therefore, this study aimed to investigate the role of ATG5 in DOX-induced cardiac toxicity. Mice were intravenously administered DOX (5 mg/kg) for 4 weeks to establish a cardiac toxicity model. Heart function was determined using echocardiography, and cardiac tissue was assessed for protein expression, mRNA levels, fibrosis, and immunofluorescent staining. DOX treatment upregulated autophagy-related gene expression but inhibited autophagic flux in vitro and in vivo. DOX–treated mice exhibited decreased heart function and cardiomyocyte size and increased cardiac fibrosis, oxidative stress, and apoptosis. These effects of DOX were partially alleviated by rAAV9 expressing shRNA-ATG5 and deteriorated by rAAV9-ATG5. We demonstrated that genetic ATG5 knockdown or autophagy inhibition by chemical inhibitors increased GATA4 protein expression, which was reduced by ATG5 overexpression or autophagy activator in vitro and in vivo, suggesting that ATG5-mediated autophagy promoted GATA4 degradation. Moreover, enforced GATA4 re-expression significantly counteracted the toxic effects of ATG5 on DOX-treated hearts. In conclusion, our study demonstrated that manipulating ATG5 expression to regulate GATA4 degradation in the heart may be a promising approach for DOX-induced cardiac toxicity. |
| format | Article |
| id | doaj-art-03f8a356552a4387bf3fe7da1358685d |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-03f8a356552a4387bf3fe7da1358685d2025-01-27T14:11:40ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.14963801496380Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradationAi-Li Xu0Zheng Shen1Shi-Hao Wang2Hai-Yun Luan3Yong Xu4Ze-Chun Kang5Zi-Qi Liao6Jie Liu7Xiao-Lei Duan8Wei-Hua Bian9Hui Sun10Xin Xie11Department of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDepartment of Cardiology, The Binzhou Affiliated Hospital, Binzhou Medical University, Binzhou, ChinaDoxorubicin (DOX) is a prevalent chemotherapeutic drug for treating several malignancies. However, the mechanisms of DOX induced cardiac toxicity is not fully understood. Previous studies have demonstrated that autophagy activation is essential in DOX-induced cardiac toxicity. Nevertheless, studies on the role of autophagy protein 5 (ATG5) in DOX-induced cardiac toxicity remain limited. Therefore, this study aimed to investigate the role of ATG5 in DOX-induced cardiac toxicity. Mice were intravenously administered DOX (5 mg/kg) for 4 weeks to establish a cardiac toxicity model. Heart function was determined using echocardiography, and cardiac tissue was assessed for protein expression, mRNA levels, fibrosis, and immunofluorescent staining. DOX treatment upregulated autophagy-related gene expression but inhibited autophagic flux in vitro and in vivo. DOX–treated mice exhibited decreased heart function and cardiomyocyte size and increased cardiac fibrosis, oxidative stress, and apoptosis. These effects of DOX were partially alleviated by rAAV9 expressing shRNA-ATG5 and deteriorated by rAAV9-ATG5. We demonstrated that genetic ATG5 knockdown or autophagy inhibition by chemical inhibitors increased GATA4 protein expression, which was reduced by ATG5 overexpression or autophagy activator in vitro and in vivo, suggesting that ATG5-mediated autophagy promoted GATA4 degradation. Moreover, enforced GATA4 re-expression significantly counteracted the toxic effects of ATG5 on DOX-treated hearts. In conclusion, our study demonstrated that manipulating ATG5 expression to regulate GATA4 degradation in the heart may be a promising approach for DOX-induced cardiac toxicity.https://www.frontiersin.org/articles/10.3389/fphar.2024.1496380/fullAtg5autophagycardiac toxicitydoxorubicinoxidative stress |
| spellingShingle | Ai-Li Xu Zheng Shen Shi-Hao Wang Hai-Yun Luan Yong Xu Ze-Chun Kang Zi-Qi Liao Jie Liu Xiao-Lei Duan Wei-Hua Bian Hui Sun Xin Xie Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation Frontiers in Pharmacology Atg5 autophagy cardiac toxicity doxorubicin oxidative stress |
| title | Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation |
| title_full | Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation |
| title_fullStr | Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation |
| title_full_unstemmed | Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation |
| title_short | Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation |
| title_sort | knockdown atg5 gene by raav9 alleviates doxorubicin induced cardiac toxicity by inhibiting gata4 autophagic degradation |
| topic | Atg5 autophagy cardiac toxicity doxorubicin oxidative stress |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1496380/full |
| work_keys_str_mv | AT ailixu knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT zhengshen knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT shihaowang knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT haiyunluan knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT yongxu knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT zechunkang knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT ziqiliao knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT jieliu knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT xiaoleiduan knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT weihuabian knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT huisun knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation AT xinxie knockdownatg5genebyraav9alleviatesdoxorubicininducedcardiactoxicitybyinhibitinggata4autophagicdegradation |