LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization

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

Redox Biology (Oct 2022)

LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization

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

Affiliations

Yijin Chen: 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
Guangkai Wu: 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
Mengsha Li: 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; Guizhou University Hospital, Guiyang Guizhou, 550025, China
Michael Hesse: Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Bonn, Germany
Yusheng Ma: 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
Wei Chen: 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
Haoxiang Huang: 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
Yu Liu: 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
Wenlong Xu: 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
Yating Tang: 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
Hao Zheng: 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
Chuling Li: 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
Zhongqiu Lin: 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
Guojun Chen: 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
Wangjun Liao: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
Yulin Liao: 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
Jianping Bin: 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.
Yanmei Chen: 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.

Journal volume & issue: Vol. 56
p. 102446

Abstract

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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.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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