Academic Journal
Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation
| العنوان: | Knockdown ATG5 gene by rAAV9 alleviates doxorubicin-induced cardiac toxicity by inhibiting GATA4 autophagic degradation |
|---|---|
| المؤلفون: | Xu, Ai-Li, Shen, Zheng, Wang, Shi-Hao, Luan, Hai-Yun, Xu, Yong, Kang, Ze-Chun, Liao, Zi-Qi, Liu, Jie, Duan, Xiao-Lei, Bian, Wei-Hua, Sun, Hui, Xie, Xin |
| المساهمون: | National Natural Science Foundation of China, Natural Science Foundation of Liaoning Province |
| المصدر: | Frontiers in Pharmacology ; volume 15 ; ISSN 1663-9812 |
| بيانات النشر: | Frontiers Media SA |
| سنة النشر: | 2025 |
| المجموعة: | Frontiers (Publisher - via CrossRef) |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| DOI: | 10.3389/fphar.2024.1496380 |
| DOI: | 10.3389/fphar.2024.1496380/full |
| الاتاحة: | https://doi.org/10.3389/fphar.2024.1496380 https://www.frontiersin.org/articles/10.3389/fphar.2024.1496380/full |
| Rights: | https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.20D2C35 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3389/fphar.2024.1496380 |
|---|