Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice
BackgroundThe increased myocardial vulnerability that occurs in diabetic patients following an ischemia-reperfusion injury (I/RI) represents a significant perioperative safety risk. A comprehensive understanding of the intrinsic mechanisms underlying this phenomenon is therefore of paramount importa...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1506401/full |
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| author | Jiyao Zhao Wei Shi Yan Zheng Junjie Wang Muzhao Yuan Yultuz Anwar Yuxuan He Haiping Ma Jianjiang Wu |
| author_facet | Jiyao Zhao Wei Shi Yan Zheng Junjie Wang Muzhao Yuan Yultuz Anwar Yuxuan He Haiping Ma Jianjiang Wu |
| author_sort | Jiyao Zhao |
| collection | DOAJ |
| description | BackgroundThe increased myocardial vulnerability that occurs in diabetic patients following an ischemia-reperfusion injury (I/RI) represents a significant perioperative safety risk. A comprehensive understanding of the intrinsic mechanisms underlying this phenomenon is therefore of paramount importance.PurposesThe objective of this study is to investigate the potential mechanism of action between impaired autophagic flux and increased vulnerability in diabetic myocardium. This will provide a foundation for the clinical search for effective preventive and curative measures.MethodsThe transcriptomic alterations in autophagy-related genes following myocardial exposure to I/RI were analyzed by single-cell sequencing. This was followed by the validation of potential mechanisms of action between impaired autophagic flux and increased susceptibility at the cellular and animal levels, respectively.ResultsAfter I/RI in diabetic myocardium, there was a significant increase in the number of CM1 subgroups and a specific downregulation of 239 autophagy-related genes led by RILP. HE staining revealed that myocardial injury was exacerbated in diabetic mice subjected to I/RI. Transmission electron microscopy revealed that the accumulation of autophagic vesicles in cardiomyocytes of diabetic mice resulted in impaired autophagic flux. qRT-PCR revealed that the expression of RILP was significantly reduced in diabetic mice subjected to I/RI. WB showed that P62 was significantly increased and RILP was significantly decreased in diabetic mice subjected to I/RI compared to healthy mice. Inhibition of mTOR during hypoxia/reoxygenation (H/R) injury restored RILP expression and attenuated cellular injury in cardiomyocytes cultured with high glucose.ConclusionFollowing I/RI in diabetic myocardium, an increase in the CM1 subpopulation and a reduction in RILP expression result in impaired autophagic flux. Regulation of the mTOR/RILP pathway can restore impaired autophagic flux and improve myocardial vulnerability, thereby exerting cardioprotective effects. |
| format | Article |
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| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-8eb755aa1d924972a29a547cadf786702025-01-31T06:39:44ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.15064011506401Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic miceJiyao Zhao0Wei Shi1Yan Zheng2Junjie Wang3Muzhao Yuan4Yultuz Anwar5Yuxuan He6Haiping Ma7Jianjiang Wu8Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaCatheterization Laboratory, Changji Prefecture People’s Hospital, Changji Hui Autonomous Prefecture, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaDepartment of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, ChinaBackgroundThe increased myocardial vulnerability that occurs in diabetic patients following an ischemia-reperfusion injury (I/RI) represents a significant perioperative safety risk. A comprehensive understanding of the intrinsic mechanisms underlying this phenomenon is therefore of paramount importance.PurposesThe objective of this study is to investigate the potential mechanism of action between impaired autophagic flux and increased vulnerability in diabetic myocardium. This will provide a foundation for the clinical search for effective preventive and curative measures.MethodsThe transcriptomic alterations in autophagy-related genes following myocardial exposure to I/RI were analyzed by single-cell sequencing. This was followed by the validation of potential mechanisms of action between impaired autophagic flux and increased susceptibility at the cellular and animal levels, respectively.ResultsAfter I/RI in diabetic myocardium, there was a significant increase in the number of CM1 subgroups and a specific downregulation of 239 autophagy-related genes led by RILP. HE staining revealed that myocardial injury was exacerbated in diabetic mice subjected to I/RI. Transmission electron microscopy revealed that the accumulation of autophagic vesicles in cardiomyocytes of diabetic mice resulted in impaired autophagic flux. qRT-PCR revealed that the expression of RILP was significantly reduced in diabetic mice subjected to I/RI. WB showed that P62 was significantly increased and RILP was significantly decreased in diabetic mice subjected to I/RI compared to healthy mice. Inhibition of mTOR during hypoxia/reoxygenation (H/R) injury restored RILP expression and attenuated cellular injury in cardiomyocytes cultured with high glucose.ConclusionFollowing I/RI in diabetic myocardium, an increase in the CM1 subpopulation and a reduction in RILP expression result in impaired autophagic flux. Regulation of the mTOR/RILP pathway can restore impaired autophagic flux and improve myocardial vulnerability, thereby exerting cardioprotective effects.https://www.frontiersin.org/articles/10.3389/fphar.2024.1506401/fulldiabetic cardiomyopathyautophagic fluxvulnerabilitymTOR/RILP pathwaymyocardial protection |
| spellingShingle | Jiyao Zhao Wei Shi Yan Zheng Junjie Wang Muzhao Yuan Yultuz Anwar Yuxuan He Haiping Ma Jianjiang Wu Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice Frontiers in Pharmacology diabetic cardiomyopathy autophagic flux vulnerability mTOR/RILP pathway myocardial protection |
| title | Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice |
| title_full | Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice |
| title_fullStr | Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice |
| title_full_unstemmed | Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice |
| title_short | Mechanism of mTOR/RILP-regulated autophagic flux in increased susceptibility to myocardial ischemia-reperfusion in diabetic mice |
| title_sort | mechanism of mtor rilp regulated autophagic flux in increased susceptibility to myocardial ischemia reperfusion in diabetic mice |
| topic | diabetic cardiomyopathy autophagic flux vulnerability mTOR/RILP pathway myocardial protection |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1506401/full |
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