Serpina3k lactylation protects from cardiac ischemia reperfusion injury
Abstract Lactate produced during ischemia-reperfusion injury is known to promote lactylation of proteins, which play controversial roles. By analyzing the lactylomes and proteomes of mouse myocardium during ischemia-reperfusion injury using mass spectrometry, we show that both Serpina3k protein expr...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55589-w |
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| author | Le Wang Dandan Li Fang Yao Shanshan Feng Chao Tong Rongjia Rao Meiyan Zhong Xianqiang Wang Wei Feng Zhan Hu Bo Jin Li Wang Shengshou Hu Bingying Zhou |
| author_facet | Le Wang Dandan Li Fang Yao Shanshan Feng Chao Tong Rongjia Rao Meiyan Zhong Xianqiang Wang Wei Feng Zhan Hu Bo Jin Li Wang Shengshou Hu Bingying Zhou |
| author_sort | Le Wang |
| collection | DOAJ |
| description | Abstract Lactate produced during ischemia-reperfusion injury is known to promote lactylation of proteins, which play controversial roles. By analyzing the lactylomes and proteomes of mouse myocardium during ischemia-reperfusion injury using mass spectrometry, we show that both Serpina3k protein expression and its lactylation at lysine 351 are increased upon reperfusion. Both Serpina3k and its human homolog, SERPINA3, are abundantly expressed in cardiac fibroblasts, but not in cardiomyocytes. Biochemically, lactylation of Serpina3k enhances protein stability. Using Serpina3k knockout mice and mice overexpressing its lactylation-deficient mutant, we find that Serpina3k protects from cardiac injury in a lysine 351 lactylation-dependent manner. Mechanistically, ischemia-reperfusion-stimulated fibroblasts secrete Serpina3k/SERPINA3, and protect cardiomyocytes from reperfusion-induced apoptosis in a paracrine fashion, partially through the activation of cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways. Our results demonstrate the pivotal role of protein lactylation in cardiac ischemia-reperfusion injury, which may hold therapeutic value. |
| format | Article |
| id | doaj-art-ea9fe56241ad492d9c9af2010ee3c38f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ea9fe56241ad492d9c9af2010ee3c38f2025-01-26T12:42:01ZengNature PortfolioNature Communications2041-17232025-01-0116112110.1038/s41467-024-55589-wSerpina3k lactylation protects from cardiac ischemia reperfusion injuryLe Wang0Dandan Li1Fang Yao2Shanshan Feng3Chao Tong4Rongjia Rao5Meiyan Zhong6Xianqiang Wang7Wei Feng8Zhan Hu9Bo Jin10Li Wang11Shengshou Hu12Bingying Zhou13State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, ShenzhenDepartment of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Cardiac Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Clinical Laboratory, Peking University First HospitalState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeState Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Lactate produced during ischemia-reperfusion injury is known to promote lactylation of proteins, which play controversial roles. By analyzing the lactylomes and proteomes of mouse myocardium during ischemia-reperfusion injury using mass spectrometry, we show that both Serpina3k protein expression and its lactylation at lysine 351 are increased upon reperfusion. Both Serpina3k and its human homolog, SERPINA3, are abundantly expressed in cardiac fibroblasts, but not in cardiomyocytes. Biochemically, lactylation of Serpina3k enhances protein stability. Using Serpina3k knockout mice and mice overexpressing its lactylation-deficient mutant, we find that Serpina3k protects from cardiac injury in a lysine 351 lactylation-dependent manner. Mechanistically, ischemia-reperfusion-stimulated fibroblasts secrete Serpina3k/SERPINA3, and protect cardiomyocytes from reperfusion-induced apoptosis in a paracrine fashion, partially through the activation of cardioprotective reperfusion injury salvage kinase and survivor activating factor enhancement pathways. Our results demonstrate the pivotal role of protein lactylation in cardiac ischemia-reperfusion injury, which may hold therapeutic value.https://doi.org/10.1038/s41467-024-55589-w |
| spellingShingle | Le Wang Dandan Li Fang Yao Shanshan Feng Chao Tong Rongjia Rao Meiyan Zhong Xianqiang Wang Wei Feng Zhan Hu Bo Jin Li Wang Shengshou Hu Bingying Zhou Serpina3k lactylation protects from cardiac ischemia reperfusion injury Nature Communications |
| title | Serpina3k lactylation protects from cardiac ischemia reperfusion injury |
| title_full | Serpina3k lactylation protects from cardiac ischemia reperfusion injury |
| title_fullStr | Serpina3k lactylation protects from cardiac ischemia reperfusion injury |
| title_full_unstemmed | Serpina3k lactylation protects from cardiac ischemia reperfusion injury |
| title_short | Serpina3k lactylation protects from cardiac ischemia reperfusion injury |
| title_sort | serpina3k lactylation protects from cardiac ischemia reperfusion injury |
| url | https://doi.org/10.1038/s41467-024-55589-w |
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