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

Chen, Yijin; Wu, Guangkai; Li, Mengsha; Hesse, Michael; Ma, Yusheng; Chen, Wei; Huang, Hongyun; Liu, Yu; Xu, Wenlong; Tang, Yating; Zheng, Hao; Li, Chuling; Lin, Zhongqiu; Chen, Guojun; Liao, Wangjun; Liao, Yulin; Bin, Jianping; Chen, Yanmei

doi:10.1016/j.redox.2022.102446

Cited by 41 publications

(22 citation statements)

References 50 publications

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“…Since both LDHA and LDHB are required for the Warburg effect [50] and LDHA has also been reported to play a role in NSCLC [51] and in ROS alleviation [52], we investigated whether LDHA has similar function as LDHB in ferroptosis defense. LDHA KD did not appear to affect STAT1 expression or the sensitivity to the ferroptosis inducers RSL3 and Erastin in A549 and H838 cells ( Supplementary Figure 5a, b, c ), as did the LDHA inhibitors (GSK2837808A and R-GNE-140) ( Supplementary Figure 5d, e ), suggesting that LDHA is not involved in ferroptosis surveillance in KRAS-mutant NSCLC.…”

Section: Resultsmentioning

confidence: 99%

A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis inKRAS-driven lung cancer

Zhao

Deng

Zhang

et al. 2023

Preprint

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Ferroptosis, a form of non-apoptotic cell death program driven by excessive lipid peroxidation and an important mechanism of tumor suppression, is frequently dysregulated in cancer. However, the mechanisms underlying impaired ferroptosis in oncogene-specific tumors remain poorly understood. Here we report a non-canonical role of lactate dehydrogenase B (LDHB), whose main activity is the conversion of lactate to pyruvate, in protecting KRAS-mutated lung cancer from ferroptosis. Silencing of LDHB impairs intracellular glutathione (GSH) metabolism and drives the hypersensitivity of KRAS-mutant cells to ferroptosis inducers by inhibiting the SLC7A11/GSH/GPX4 axis, a central antioxidant system against lipid peroxidation and ferroptosis by catalyzing GSH synthesis and utilization. Mechanistically, LDHB promotes SLC7A11 expression and GSH biosynthesis, and inhibition of LDHB confers metabolic synthetic lethality with ferroptosis inducers due to increased glutaminolysis and production of reactive oxygen species (ROS) in mitochondria, ultimately triggering ferroptosis of KRAS-driven lung cancer cells. Consequently, combined inhibition of LDHB and SLC7A11 synergistically suppresses tumor growth in multiple KRAS-mutant lung cancer implants and in an autochthonous model of Kras-induced lung adenocarcinoma. Taken together, our results reveal a hitherto unrecognized mechanism of ferroptosis defense by glycolytic LDHB and suggest a new strategy for the treatment of KRAS-dependent lung cancer.

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Section: Resultsmentioning

confidence: 99%

A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis inKRAS-driven lung cancer

Zhao

Deng

Zhang

et al. 2023

Preprint

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“…Gene expression of marker genes for zymosan challenge was also higher in GM-Macs. Some redox genes ( Prdx1 and Prdx6) , genes involved in lipid and cholesterol metabolism ( Hilpda, Er1l) 76,77 , stress response and cell death ( Hk2, Pgk1 ) 78,79 as well as M2 macrophage activation ( Ldha ) 80 demonstrated overlap with transcriptional response to zymosan, and showed higher upregulation in both cell types infected with PTG parasites 12 hpi. (figure 5c).…”

Section: Resultsmentioning

confidence: 99%

scDual-Seq ofToxoplasma gondii-infected mouse bone marrow-derived dendritic cells reveals host cell heterogeneity and differential infection dynamics

Hildebrandt

Mohammed

Dziedziech

et al. 2023

Preprint

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Host-parasite interactions include complex interplays between an invading and a defending organism, each continuously adapting to gain the upper hand. The protozoan parasite, Toxoplasma gondii, can invade every nucleated cell type in a vertebrate host, including immune cells while the host mounts a protective response. Here, we utilize Dual-scSeq to parse out heterogeneous transcription of bone marrow-derived dendritic cells (BMDCs) infected with T. gondii type I, RH (LDM) or type II, ME49 (PTG) parasites, over multiple time points post infection. We find that the two parasite lineages distinctly manipulate two subpopulations of infected BMDCs. Co-expression networks establish host and parasite genes, with implications for modulation of host immunity and host-pathogen interactions. Integration of published data validates immune pathways and suggests novel candidate genes involved in host-pathogen interactions. This study aims to provide a comprehensive resource for future characterization of host-pathogen interplay among other protozoan parasites within their host niches, as well as that of bacterial and viral pathogens.

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“…Recent studies have demonstrated that LDH-A has a close relationship with cardiovascular diseases and may be a potential therapeutic target for heart failure and pulmonary hypertension [27,28]. It has also been demonstrated that LDH-A-driven lactate may create a microenvironment bene cial to cardiac regeneration [29]. These ndings suggest that targeting metabolic reprogramming through LDH-A might be an effective protection strategy for cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Mellitus Are Less Likely to Aortic Dissection: A 5-Year Single-Center Analysis on independent risk factors of Aortic Dissection in Diabetes Mellitus Patients

Yang

Chen²,

Wu³

et al. 2022

Preprint

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Background Diabetes mellitus (DM) is a severe risk factor in most cardiovascular diseases, but is negatively associated with the incidence of acute aortic dissection (AAD). The purpose of this study was to explore the independent risk factors for DM patients who are still with AAD and to establish a nomogram model to predict the risk of AAD in DM patients. Methods Clinical data on 364 DM patients who got surgical indications was collected from January 2016 to December 2021. These patients were divided into negative and positive cohorts according to the diagnosis of AAD. The logistic proportional hazards model was used to find out the risk factors related to DM patients with AAD. A nomogram was generated based on the contribution weights of the independent risk factors. AD mice model was constructed to verify related risk factors in vivo. Results Among 364 patients, AAD occurred in 25 (6.87%) patients. Multivariable logistic regression analysis showed that, after adjusting for confounders, preoperative LDH, hypertension, BMI, and coronary heart disease (CHD) were all positively associated with the risk of AAD in DM patients. (LDH: OR:1.003, 95% Cl: 1.001–1005, p = 0.002; CHD: OR:3.591, 95% Cl: 1.142–11.289, p = 0.029; Hypertension: OR:2.854, 95% Cl: 1.087–7.494, p = 0.033; BMI: OR:1.184, 95% Cl: 1.029–1362, p = 0.018). Pharmacological inhibition of LDH in AAD mice was able to decrease the incidence of AAD from 43.75–13.33%. Conclusion DM patients were negatively associated with AAD, but dysregulated preoperative-LDH、BMI、hypertension and CHD are risk factors for AAD in DM patients.

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

Cited by 41 publications

References 50 publications

A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis inKRAS-driven lung cancer

A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis inKRAS-driven lung cancer

scDual-Seq ofToxoplasma gondii-infected mouse bone marrow-derived dendritic cells reveals host cell heterogeneity and differential infection dynamics

Diabetes Mellitus Are Less Likely to Aortic Dissection: A 5-Year Single-Center Analysis on independent risk factors of Aortic Dissection in Diabetes Mellitus Patients

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