LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization.
LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation by alleviating ROS and inducing M2 macrophage polarization.
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乳酸脱氢酶A（LDHA）介导的代谢重编程通过减轻活性氧（ROS）并诱导M2型巨噬细胞极化来促进心肌细胞增殖。
DOI：
10.1016/j.redox.2022.102446
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发表时间：
2022-10
期刊：
影响因子：
11.4
通讯作者：
Chen, Yanmei
中科院分区：
文献类型：
--
作者：
Chen, Yijin;Wu, Guangkai;Li, Mengsha;Hesse, Michael;Ma, Yusheng;Chen, Wei;Huang, Haoxiang;Liu, Yu;Xu, Wenlong;Tang, Yating;Zheng, Hao;Li, Chuling;Lin, Zhongqiu;Chen, Guojun;Liao, Wangjun;Liao, Yulin;Bin, Jianping;Chen, Yanmei
心脏发育过程中的代谢转换导致出生后心肌细胞(CM)细胞周期的退出和哺乳动物心脏再生能力的丧失。代谢控制具有开发有效的CM增殖策略的潜力。我们试图确定乳酸脱氢酶A(LDHA)是否通过诱导代谢重编程来调节CM的增殖。低密度脂蛋白(LDHA)在出生后心脏发育过程中高表达，在出生后心脏发育过程中显著降低。采用CRISPR/Cas9技术建立CM特异性LDHA基因敲除小鼠。在新生儿心尖切除术模型中，CM特异性LDHA基因敲除抑制了CM的增殖，导致心功能恶化和存活率降低。相反，CM特异性的LDHA过表达促进了心肌梗死后的CM增殖和心脏修复。用α-MHC-H_2B-MCH/CAG-EGFP-苯丙氨酸体系证实LDHA对P7CMS和成人心脏的促增殖作用。代谢组学、蛋白质组学和Co-IP实验表明，LDHA介导的琥珀酰辅酶A还原抑制了依赖琥珀酸化的硫氧还蛋白还原酶1(Txnrd1)的泛素化，从而减轻了ROS，从而促进了CM的增殖。此外，流式细胞术和Western blotting显示，LDHA驱动的乳酸产生通过诱导M2巨噬细胞极化而创造了有利的心脏再生微环境。LDHA介导的代谢重编程通过减轻ROS和诱导M2巨噬细胞极化来促进CM增殖，提示LDHA可能是促进心肌梗死后心脏修复的有效靶点。琥珀酸化依赖的Txnrd1泛素化是LDHA介导的减轻心肌细胞增殖过程中ROS的一种新机制。LDHA驱动的乳酸产生通过诱导M2巨噬细胞极化创造了一个有益的心脏再生微环境。LDHA介导的代谢重编程促进心肌细胞增殖，提示LDHA可能是促进心肌梗死后心脏修复的治疗靶点。
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. 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. 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. Succinylation-dependent ubiquitination of Txnrd1 is a new mechanism involved in LDHA-mediated ROS alleviation during cardiomyocyte proliferation. LDHA-driven lactate production created a beneficial cardiac regenerative microenvironment by inducing M2 macrophage polarization. LDHA-mediated metabolic reprogramming promoted cardiomyocyte proliferation, indicating that LDHA might be a therapeutic target to promote cardiac repair post-MI.
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影响因子：
21.3
作者：
Flores A;Schell J;Krall AS;Jelinek D;Miranda M;Grigorian M;Braas D;White AC;Zhou JL;Graham NA;Graeber T;Seth P;Evseenko D;Coller HA;Rutter J;Christofk HR;Lowry WE
通讯作者：
Lowry WE
影响因子：
37.8
作者：
Bae J;Salamon RJ;Brandt EB;Paltzer WG;Zhang Z;Britt EC;Hacker TA;Fan J;Mahmoud AI
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Mahmoud AI
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影响因子：
4.6
作者：
Fajardo VM;Feng I;Chen BY;Perez-Ramirez CA;Shi B;Clark P;Tian R;Lien CL;Pellegrini M;Christofk H;Nakano H;Nakano A
通讯作者：
Nakano A
影响因子：
20.8
作者：
Cardoso, Alisson C.;Lam, Nicholas T.;Sadek, Hesham A.
通讯作者：
Sadek, Hesham A.
影响因子：
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作者：
Hasan, Md. Mehedi;Yang, Shiping;Mollah, Md. Nurul Haque
通讯作者：
Mollah, Md. Nurul Haque