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Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress
Sirtuin 1 (Sirt1) exerts its cardioprotective effects in various cardiovascular diseases via multiple cellular activities. However, the therapeutic implications of Sirt1 in hypoxic cardiomyocytes and the underlying mechanisms remain elusive. The present study investigated whether Sirt1 regulates aut...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443335/ https://www.ncbi.nlm.nih.gov/pubmed/30864731 http://dx.doi.org/10.3892/ijmm.2019.4125 |
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author | Luo, Guiping Jian, Zhao Zhu, Yun Zhu, Yu Chen, Baicheng Ma, Ruiyan Tang, Fuqin Xiao, Yingbin |
author_facet | Luo, Guiping Jian, Zhao Zhu, Yun Zhu, Yu Chen, Baicheng Ma, Ruiyan Tang, Fuqin Xiao, Yingbin |
author_sort | Luo, Guiping |
collection | PubMed |
description | Sirtuin 1 (Sirt1) exerts its cardioprotective effects in various cardiovascular diseases via multiple cellular activities. However, the therapeutic implications of Sirt1 in hypoxic cardiomyocytes and the underlying mechanisms remain elusive. The present study investigated whether Sirt1 regulates autophagy and apoptosis in hypoxic H9C2 cardiomyocytes and in an experimental hypoxic mouse model. Right ventricular outflow tract biopsies were obtained from patients with cyanotic or acyanotic congenital heart diseases. Adenovirus Ad-Sirt1 was used to activate Sirt1 and Ad-Sh-Sirt1 was used to inhibit Sirt1 expression in H9C2 cells, in order to investigate the effect of Sirt1 on cellular autophagy and apoptosis. SRT1720, a pharmacological activator of Sirt1 and EX-527, a Sirt1 antagonist, were administered to mice to explore the role of Sirt1 in hypoxic cardiomyocytes in vivo. The levels of autophagy and apoptosis-related proteins were evaluated using western blotting. Apoptosis was investigated by TUNEL staining and Annexin V/7-aminoactinomycin D flow cytometry analysis. Heart tissue samples from cyanotic patients exhibited increased autophagy and apoptosis, as well as elevated Sirt1 levels, compared with the noncyanotic control samples. The data from the western blot analysis revealed that Sirt1 promoted autophagic flux and reduced apoptosis in hypoxic H9C2 cells. In addition, Sirt1 activated AMP-activated protein kinase (AMPK), and the AMPK inhibitor Compound C abolished the effect of Sirt1 on autophagy activation. Further exploration of the mechanism revealed that Sirt1 protects hypoxic cardiomyocytes from apoptosis, at least in part, through inositol requiring kinase enzyme 1α (IRE1α). Consistent with the in vitro results, treatment with the Sirt1 activator SRT1720 activated AMPK, inhibited IRE1α, enhanced autophagy, and decreased apoptosis in the heart tissues of normoxic mice compared with the hypoxia control group. Opposite changes were observed in hypoxic mice treated with the Sirt1 inhibitor EX-527. These results suggested that Sirt1 promoted autophagy via AMPK activation and reduced hypoxia-induced apoptosis via the IRE1α pathway, to protect cardiomyocytes from hypoxic stress. |
format | Online Article Text |
id | pubmed-6443335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-64433352019-04-03 Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress Luo, Guiping Jian, Zhao Zhu, Yun Zhu, Yu Chen, Baicheng Ma, Ruiyan Tang, Fuqin Xiao, Yingbin Int J Mol Med Articles Sirtuin 1 (Sirt1) exerts its cardioprotective effects in various cardiovascular diseases via multiple cellular activities. However, the therapeutic implications of Sirt1 in hypoxic cardiomyocytes and the underlying mechanisms remain elusive. The present study investigated whether Sirt1 regulates autophagy and apoptosis in hypoxic H9C2 cardiomyocytes and in an experimental hypoxic mouse model. Right ventricular outflow tract biopsies were obtained from patients with cyanotic or acyanotic congenital heart diseases. Adenovirus Ad-Sirt1 was used to activate Sirt1 and Ad-Sh-Sirt1 was used to inhibit Sirt1 expression in H9C2 cells, in order to investigate the effect of Sirt1 on cellular autophagy and apoptosis. SRT1720, a pharmacological activator of Sirt1 and EX-527, a Sirt1 antagonist, were administered to mice to explore the role of Sirt1 in hypoxic cardiomyocytes in vivo. The levels of autophagy and apoptosis-related proteins were evaluated using western blotting. Apoptosis was investigated by TUNEL staining and Annexin V/7-aminoactinomycin D flow cytometry analysis. Heart tissue samples from cyanotic patients exhibited increased autophagy and apoptosis, as well as elevated Sirt1 levels, compared with the noncyanotic control samples. The data from the western blot analysis revealed that Sirt1 promoted autophagic flux and reduced apoptosis in hypoxic H9C2 cells. In addition, Sirt1 activated AMP-activated protein kinase (AMPK), and the AMPK inhibitor Compound C abolished the effect of Sirt1 on autophagy activation. Further exploration of the mechanism revealed that Sirt1 protects hypoxic cardiomyocytes from apoptosis, at least in part, through inositol requiring kinase enzyme 1α (IRE1α). Consistent with the in vitro results, treatment with the Sirt1 activator SRT1720 activated AMPK, inhibited IRE1α, enhanced autophagy, and decreased apoptosis in the heart tissues of normoxic mice compared with the hypoxia control group. Opposite changes were observed in hypoxic mice treated with the Sirt1 inhibitor EX-527. These results suggested that Sirt1 promoted autophagy via AMPK activation and reduced hypoxia-induced apoptosis via the IRE1α pathway, to protect cardiomyocytes from hypoxic stress. D.A. Spandidos 2019-05 2019-03-06 /pmc/articles/PMC6443335/ /pubmed/30864731 http://dx.doi.org/10.3892/ijmm.2019.4125 Text en Copyright: © Luo et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Luo, Guiping Jian, Zhao Zhu, Yun Zhu, Yu Chen, Baicheng Ma, Ruiyan Tang, Fuqin Xiao, Yingbin Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress |
title | Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress |
title_full | Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress |
title_fullStr | Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress |
title_full_unstemmed | Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress |
title_short | Sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress |
title_sort | sirt1 promotes autophagy and inhibits apoptosis to protect cardiomyocytes from hypoxic stress |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443335/ https://www.ncbi.nlm.nih.gov/pubmed/30864731 http://dx.doi.org/10.3892/ijmm.2019.4125 |
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