LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization
Aims: Metabolic switching during heart development contributes to postnatal cardiomyocyte (CM) cell cycle exit and loss of regenerative capacity in the mammalian heart. Metabolic control has potential for developing effective CM proliferation strategies. We sought to determine whether lactate dehydr...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172200218X |
| _version_ | 1811267026334777344 |
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| author | Yijin Chen Guangkai Wu Mengsha Li Michael Hesse Yusheng Ma Wei Chen Haoxiang Huang Yu Liu Wenlong Xu Yating Tang Hao Zheng Chuling Li Zhongqiu Lin Guojun Chen Wangjun Liao Yulin Liao Jianping Bin Yanmei Chen |
| author_facet | Yijin Chen Guangkai Wu Mengsha Li Michael Hesse Yusheng Ma Wei Chen Haoxiang Huang Yu Liu Wenlong Xu Yating Tang Hao Zheng Chuling Li Zhongqiu Lin Guojun Chen Wangjun Liao Yulin Liao Jianping Bin Yanmei Chen |
| author_sort | Yijin Chen |
| collection | DOAJ |
| description | Aims: Metabolic switching during heart development contributes to postnatal cardiomyocyte (CM) cell cycle exit and loss of regenerative capacity in the mammalian heart. Metabolic control has potential for developing effective CM proliferation strategies. We sought to determine whether lactate dehydrogenase A (LDHA) regulated CM proliferation by inducing metabolic reprogramming. Methods and results: LDHA expression was high in P1 hearts and significantly decreased during postnatal heart development. CM-specific LDHA knockout mice were generated using CRISPR/Cas9 technology. CM-specific LDHA knockout inhibited CM proliferation, leading to worse cardiac function and a lower survival rate in the neonatal apical resection model. In contrast, CM-specific overexpression of LDHA promoted CM proliferation and cardiac repair post-MI. The α-MHC-H2B-mCh/CAG-eGFP-anillin system was used to confirm the proliferative effect triggered by LDHA on P7 CMs and adult hearts. Metabolomics, proteomics and Co-IP experiments indicated that LDHA-mediated succinyl coenzyme A reduction inhibited succinylation-dependent ubiquitination of thioredoxin reductase 1 (Txnrd1), which alleviated ROS and thereby promoted CM proliferation. In addition, flow cytometry and western blotting showed that LDHA-driven lactate production created a beneficial cardiac regenerative microenvironment by inducing M2 macrophage polarization. Conclusions: LDHA-mediated metabolic reprogramming promoted CM proliferation by alleviating ROS and inducing M2 macrophage polarization, indicating that LDHA might be an effective target for promoting cardiac repair post-MI. |
| first_indexed | 2024-04-12T20:53:57Z |
| format | Article |
| id | doaj.art-cbea050ec87f401b9a5a184a2000bb60 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-12T20:53:57Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-cbea050ec87f401b9a5a184a2000bb602022-12-22T03:17:02ZengElsevierRedox Biology2213-23172022-10-0156102446LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarizationYijin Chen0Guangkai Wu1Mengsha Li2Michael Hesse3Yusheng Ma4Wei Chen5Haoxiang Huang6Yu Liu7Wenlong Xu8Yating Tang9Hao Zheng10Chuling Li11Zhongqiu Lin12Guojun Chen13Wangjun Liao14Yulin Liao15Jianping Bin16Yanmei Chen17Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, China; Guizhou University Hospital, Guiyang Guizhou, 550025, ChinaInstitute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Bonn, GermanyDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, ChinaDepartment of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, China; Corresponding author. Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China.Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, 510515, Guangzhou, China; Corresponding author. Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China.Aims: Metabolic switching during heart development contributes to postnatal cardiomyocyte (CM) cell cycle exit and loss of regenerative capacity in the mammalian heart. Metabolic control has potential for developing effective CM proliferation strategies. We sought to determine whether lactate dehydrogenase A (LDHA) regulated CM proliferation by inducing metabolic reprogramming. Methods and results: LDHA expression was high in P1 hearts and significantly decreased during postnatal heart development. CM-specific LDHA knockout mice were generated using CRISPR/Cas9 technology. CM-specific LDHA knockout inhibited CM proliferation, leading to worse cardiac function and a lower survival rate in the neonatal apical resection model. In contrast, CM-specific overexpression of LDHA promoted CM proliferation and cardiac repair post-MI. The α-MHC-H2B-mCh/CAG-eGFP-anillin system was used to confirm the proliferative effect triggered by LDHA on P7 CMs and adult hearts. Metabolomics, proteomics and Co-IP experiments indicated that LDHA-mediated succinyl coenzyme A reduction inhibited succinylation-dependent ubiquitination of thioredoxin reductase 1 (Txnrd1), which alleviated ROS and thereby promoted CM proliferation. In addition, flow cytometry and western blotting showed that LDHA-driven lactate production created a beneficial cardiac regenerative microenvironment by inducing M2 macrophage polarization. Conclusions: LDHA-mediated metabolic reprogramming promoted CM proliferation by alleviating ROS and inducing M2 macrophage polarization, indicating that LDHA might be an effective target for promoting cardiac repair post-MI.http://www.sciencedirect.com/science/article/pii/S221323172200218XLDHAMetabolic reprogrammingCardiomyocyte proliferationROSMacrophage polarization |
| spellingShingle | Yijin Chen Guangkai Wu Mengsha Li Michael Hesse Yusheng Ma Wei Chen Haoxiang Huang Yu Liu Wenlong Xu Yating Tang Hao Zheng Chuling Li Zhongqiu Lin Guojun Chen Wangjun Liao Yulin Liao Jianping Bin Yanmei Chen LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization Redox Biology LDHA Metabolic reprogramming Cardiomyocyte proliferation ROS Macrophage polarization |
| title | LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization |
| title_full | LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization |
| title_fullStr | LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization |
| title_full_unstemmed | LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization |
| title_short | LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization |
| title_sort | ldha mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ros and inducing m2 macrophage polarization |
| topic | LDHA Metabolic reprogramming Cardiomyocyte proliferation ROS Macrophage polarization |
| url | http://www.sciencedirect.com/science/article/pii/S221323172200218X |
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