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

作者：Yijin Chen, 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, Yanmei Chen · 发表于：Redox Biology · 年份：2022 · DOI：10.1016/j.redox.2022.102446 · 被引用次数：129 · 研究领域：Congenital heart defects research、Tissue Engineering and Regenerative Medicine、Cardiac Fibrosis and Remodeling

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 alleviat...