Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy
Endotoxemia in sepsis remains a problem due to a lack of effective strategies. Our previous studies have demonstrated that melatonin (Mel) protects against ischemic heart injury and arteriosclerosis. However, its role in endotoxemia-exposed cardiomyocytes remains poorly understood. This study explor...
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| Format: | Article |
| Language: | English |
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Wiley
2021-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2021/8120403 |
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| author | Ya Qiu Yan Ma Min Jiang Sulei Li Jibin Zhang Haixu Chen Mengqi Xu Shan Gao Lei Tian Bo Tao Yabin Wang Dong Han Feng Cao |
| author_facet | Ya Qiu Yan Ma Min Jiang Sulei Li Jibin Zhang Haixu Chen Mengqi Xu Shan Gao Lei Tian Bo Tao Yabin Wang Dong Han Feng Cao |
| author_sort | Ya Qiu |
| collection | DOAJ |
| description | Endotoxemia in sepsis remains a problem due to a lack of effective strategies. Our previous studies have demonstrated that melatonin (Mel) protects against ischemic heart injury and arteriosclerosis. However, its role in endotoxemia-exposed cardiomyocytes remains poorly understood. This study explored, for the first time, the protective effect of Mel on the pyroptosis of human stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to lipopolysaccharide (LPS). Our results showed that treatment with 1 μM or 10 μM Mel for 12 h significantly improved 1 μg/ml LPS-induced hiPSC-CM injuries, as reflected by drastically decreased LDH release and increased cell viability, which was accompanied by the overt induction of autophagy. Specifically, Mel profoundly alleviated LPS-induced cell pyroptosis, as evidenced by decreased propidium iodide (PI) and active caspase-1 double-positive cell rates; suppressed the expression of NLRP3, cleaved caspase-1 (activated form of caspase-1), and GSDMD-NT (functional N-terminal fragment of GSDMD) expression; and inhibited the production of the cleaved IL-1β and cleaved IL-18 cytokines. Additionally, double-membrane autophagosomes were observed in LPS-injured hiPSC-CMs treated with 1 μM or 10 μM Mel. The hiPSC-CMs treated with LPS exhibited considerably fewer acidic vesicles (as revealed by LAMP1 staining) and autophagosomes (as revealed by LC3-II staining); however, Mel reversed this outcome in a dose-dependent manner. Furthermore, coincubation with rapamycin (an autophagy activator) or 3-MA (an autophagy inhibitor) accentuated and attenuated the antipyroptotic actions of Mel, respectively. Collectively, our findings demonstrate that Mel shields hiPSC-CMs against pyroptosis during endotoxemia by activating autophagy. |
| format | Article |
| id | doaj-art-5da7754a7d03440e8e50a3b2e5ad14e7 |
| institution | Kabale University |
| issn | 1687-9678 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-5da7754a7d03440e8e50a3b2e5ad14e72025-02-03T01:10:08ZengWileyStem Cells International1687-96782021-01-01202110.1155/2021/8120403Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating AutophagyYa Qiu0Yan Ma1Min Jiang2Sulei Li3Jibin Zhang4Haixu Chen5Mengqi Xu6Shan Gao7Lei Tian8Bo Tao9Yabin Wang10Dong Han11Feng Cao12Institute of GeriatricsNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterInstitute of GeriatricsNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterInstitute of GeriatricsNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterNational Clinical Research Center for Geriatric Diseases & 2nd Medical CenterEndotoxemia in sepsis remains a problem due to a lack of effective strategies. Our previous studies have demonstrated that melatonin (Mel) protects against ischemic heart injury and arteriosclerosis. However, its role in endotoxemia-exposed cardiomyocytes remains poorly understood. This study explored, for the first time, the protective effect of Mel on the pyroptosis of human stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to lipopolysaccharide (LPS). Our results showed that treatment with 1 μM or 10 μM Mel for 12 h significantly improved 1 μg/ml LPS-induced hiPSC-CM injuries, as reflected by drastically decreased LDH release and increased cell viability, which was accompanied by the overt induction of autophagy. Specifically, Mel profoundly alleviated LPS-induced cell pyroptosis, as evidenced by decreased propidium iodide (PI) and active caspase-1 double-positive cell rates; suppressed the expression of NLRP3, cleaved caspase-1 (activated form of caspase-1), and GSDMD-NT (functional N-terminal fragment of GSDMD) expression; and inhibited the production of the cleaved IL-1β and cleaved IL-18 cytokines. Additionally, double-membrane autophagosomes were observed in LPS-injured hiPSC-CMs treated with 1 μM or 10 μM Mel. The hiPSC-CMs treated with LPS exhibited considerably fewer acidic vesicles (as revealed by LAMP1 staining) and autophagosomes (as revealed by LC3-II staining); however, Mel reversed this outcome in a dose-dependent manner. Furthermore, coincubation with rapamycin (an autophagy activator) or 3-MA (an autophagy inhibitor) accentuated and attenuated the antipyroptotic actions of Mel, respectively. Collectively, our findings demonstrate that Mel shields hiPSC-CMs against pyroptosis during endotoxemia by activating autophagy.http://dx.doi.org/10.1155/2021/8120403 |
| spellingShingle | Ya Qiu Yan Ma Min Jiang Sulei Li Jibin Zhang Haixu Chen Mengqi Xu Shan Gao Lei Tian Bo Tao Yabin Wang Dong Han Feng Cao Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy Stem Cells International |
| title | Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy |
| title_full | Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy |
| title_fullStr | Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy |
| title_full_unstemmed | Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy |
| title_short | Melatonin Alleviates LPS-Induced Pyroptotic Cell Death in Human Stem Cell-Derived Cardiomyocytes by Activating Autophagy |
| title_sort | melatonin alleviates lps induced pyroptotic cell death in human stem cell derived cardiomyocytes by activating autophagy |
| url | http://dx.doi.org/10.1155/2021/8120403 |
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