Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming
Abstract Myocardial ischemia‐reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully c...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409499 |
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| author | Han She Yi Hu Guozhi Zhao Yunxia Du Yinyu Wu Wei Chen Yong Li Yi Wang Lei Tan Yuanqun Zhou Jie Zheng Qinghui Li Hong Yan Qingxiang Mao Deyu Zuo Liangming Liu Tao Li |
| author_facet | Han She Yi Hu Guozhi Zhao Yunxia Du Yinyu Wu Wei Chen Yong Li Yi Wang Lei Tan Yuanqun Zhou Jie Zheng Qinghui Li Hong Yan Qingxiang Mao Deyu Zuo Liangming Liu Tao Li |
| author_sort | Han She |
| collection | DOAJ |
| description | Abstract Myocardial ischemia‐reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK‐MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex‐treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI. |
| format | Article |
| id | doaj-art-86425db2c7aa4c3e81c5cf320c45957c |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-86425db2c7aa4c3e81c5cf320c45957c2025-08-20T02:01:00ZengWileyAdvanced Science2198-38442024-12-011148n/an/a10.1002/advs.202409499Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic ReprogrammingHan She0Yi Hu1Guozhi Zhao2Yunxia Du3Yinyu Wu4Wei Chen5Yong Li6Yi Wang7Lei Tan8Yuanqun Zhou9Jie Zheng10Qinghui Li11Hong Yan12Qingxiang Mao13Deyu Zuo14Liangming Liu15Tao Li16Department of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Urology Surgery The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaShock and Transfusion Department Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Respiratory Disease Daping Hospital Army Medical University Chongqing 400042 ChinaShock and Transfusion Department Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Anesthesiology Daping Hospital Army Medical University Chongqing 400042 ChinaDepartment of Rehabilitation Medicine The First Affiliated Hospital of Chongqing University of Chinese Medicine Chongqing Traditional Chinese Medicine Hospital Chongqing 400021 ChinaShock and Transfusion Department Daping Hospital Army Medical University Chongqing 400042 ChinaShock and Transfusion Department Daping Hospital Army Medical University Chongqing 400042 ChinaAbstract Myocardial ischemia‐reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK‐MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex‐treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1) phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.https://doi.org/10.1002/advs.202409499dexmedetomidineferroptosislactylationmetabolic reprogrammingmyocardial ischemia‐reperfusion injury |
| spellingShingle | Han She Yi Hu Guozhi Zhao Yunxia Du Yinyu Wu Wei Chen Yong Li Yi Wang Lei Tan Yuanqun Zhou Jie Zheng Qinghui Li Hong Yan Qingxiang Mao Deyu Zuo Liangming Liu Tao Li Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming Advanced Science dexmedetomidine ferroptosis lactylation metabolic reprogramming myocardial ischemia‐reperfusion injury |
| title | Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming |
| title_full | Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming |
| title_fullStr | Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming |
| title_full_unstemmed | Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming |
| title_short | Dexmedetomidine Ameliorates Myocardial Ischemia‐Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming |
| title_sort | dexmedetomidine ameliorates myocardial ischemia reperfusion injury by inhibiting mdh2 lactylation via regulating metabolic reprogramming |
| topic | dexmedetomidine ferroptosis lactylation metabolic reprogramming myocardial ischemia‐reperfusion injury |
| url | https://doi.org/10.1002/advs.202409499 |
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