Sirt6 protects cardiomyocytes against doxorubicin-induced cardiotoxicity by inhibiting P53/Fas-dependent cell death and augmenting endogenous antioxidant defense mechanisms
| العنوان: | Sirt6 protects cardiomyocytes against doxorubicin-induced cardiotoxicity by inhibiting P53/Fas-dependent cell death and augmenting endogenous antioxidant defense mechanisms |
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| المؤلفون: | Caili Zhuo, Jie Lan, Xue Li, Yao Wu, Ruli Li, Ling-yu Li, Xin Yan, Hongying Chen, Li Fu, Xuemei Chen, Juanjuan Xin, Kunyue Xue, Ming-ming Tong, He Li, Xiaoxiao Wang, Jiayi Xu, Yanjing Zhang, Sisi Wu, Wei Jiang |
| المصدر: | Cell Biology and Toxicology. 39:237-258 |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | SIRT6, Programmed cell death, Cardiotoxicity, Necrosis, biology, Chemistry, Health, Toxicology and Mutagenesis, Cell Biology, Toxicology, medicine.disease_cause, Fas ligand, Cell biology, Apoptosis, Sirtuin, medicine, biology.protein, medicine.symptom, Oxidative stress |
| الوصف: | Sirt6, a class III NAD+-dependent deacetylase of the sirtuin family, is a highly specific H3 deacetylase and plays important roles in regulating cellular growth and death. The induction of oxidative stress and death is the critical mechanism involved in cardiomyocyte injury and cardiac dysfunction in doxorubicin-induced cardiotoxicity, but the regulatory role of Sirt6 in the fate of DOX-impaired cardiomyocytes is poorly understood. In the present study, we exposed Sirt6 heterozygous (Sirt6+/−) mice and their littermates as well as cultured neonatal rat cardiomyocytes to DOX, then investigated the role of Sirt6 in mitigating oxidative stress and cardiac injury in the DOX-treated myocardium. Sirt6 partial knockout or silencing worsened cardiac damage, remodeling, and oxidative stress injury in mice or cultured cardiomyocytes with DOX challenge. Cardiomyocytes infected with adenoviral constructs encoding Sirt6 showed reversal of this DOX-induced damage. Intriguingly, Sirt6 reduced oxidative stress injury by upregulating endogenous antioxidant levels, interacted with oxidative stress-stirred p53, and acted as a co-repressor of p53 in nuclei. Sirt6 was recruited by p53 to the promoter regions of the target genes Fas and FasL and further suppressed p53 transcription activity by reducing histone acetylation. Sirt6 inhibited Fas/FasL signaling and attenuated both Fas-FADD-caspase-8 apoptotic and Fas-RIP3 necrotic pathways. These results indicate that Sirt6 protects the heart against DOX-induced cardiotoxicity by upregulating endogenous antioxidants, as well as suppressing oxidative stress and cell death signaling pathways dependent on ROS-stirred p53 transcriptional activation, thus reducing Fas–FasL-mediated apoptosis and necrosis. |
| تدمد: | 1573-6822 0742-2091 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e45dfb2b168df48b73370359c39097a5 https://doi.org/10.1007/s10565-021-09649-2 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e45dfb2b168df48b73370359c39097a5 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 15736822 07422091 |
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