Long non-coding RNA Linc00092 inhibits cardiac fibroblast activation by altering glycolysis in an ERK-dependent manner

Chen, Zhi-Teng; Zhang, Haifeng; Wang, Meng; Wang, Shaohua; Wen, Zheng; Gao, Qingyuan; Wu, Maoxiong; Liu, Wenhao; Xie, Yong; Mai, Jing-Ting; Yang, Ying; Wang, Jingfeng; Chen, Yangxin

doi:10.1016/j.cellsig.2020.109708

Cited by 20 publications

(15 citation statements)

References 45 publications

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“…Owing to the high energy demand of myofibroblasts (Li et al, 2016;Marín-Hernández et al, 2019), metabolic reprogramming and enhanced glycolysis are considered to be the drivers of fibroblast activation (Xie et al, 2015;Zhao et al, 2020). We previously obtained similar results, namely, that suppression of glycolysis can attenuate CF activation (Chen et al, 2020b). In contrast, unbalanced mitochondrial dynamics can disrupt mitochondrial energy supply.…”

Section: Figure 3 | Reducing the Cardiac Fibroblasts (Cf) Glycolytic Flux May Be Important For Mitochondrial Fission Inhibition-induced Smentioning

confidence: 64%

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RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

Gao

Zhang

Tao

et al. 2021

Front. Cell Dev. Biol.

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Although mitochondrial fission has been reported to increase proliferative capacity and collagen production, it can also contribute to mitochondrial impairment, which is detrimental to cell survival. The aim of the present study was to investigate the role of mitochondrial fission in cardiac fibroblasts (CF) activation and explore the mechanisms involved in the maintenance of mitochondrial health under this condition. For this, changes in the levels of mitochondrial fission/fusion-related proteins were assessed in transforming growth factor beta 1 (TGF-β1)-activated CF, whereas the role of mitochondrial fission during this process was also elucidated, as were the underlying mechanisms. The interaction between mitochondrial fission and mitophagy, the main defense mechanism against mitochondrial impairment, was also explored. The results showed that the mitochondria in TGF-β1-treated CF were noticeably more fragmented than those of controls. The expression of several mitochondrial fission-related proteins was markedly upregulated, and the levels of fusion-related proteins were also altered, but to a lesser extent. Inhibiting mitochondrial fission resulted in a marked attenuation of TGF-β1-induced CF activation. The TGF-β1-induced increase in glycolysis was greatly suppressed in the presence of a mitochondrial inhibitor, whereas a glycolysis-specific antagonist exerted little additional antifibrotic effects. TGF-β1 treatment increased cellular levels of reactive oxygen species (ROS) and triggered mitophagy, but this effect was reversed following the application of ROS scavengers. For the signals mediating mitophagy, the expression of Pink1, but not Bnip3l/Nix or Fundc1, exhibited the most significant changes, which could be counteracted by treatment with a mitochondrial fission inhibitor. Pink1 knockdown suppressed CF activation and mitochondrial fission, which was accompanied by increased CF apoptosis. In conclusion, mitochondrial fission resulted in increased glycolysis and played a crucial role in CF activation. Moreover, mitochondrial fission promoted reactive oxygen species (ROS) production, leading to mitophagy and the consequent degradation of the impaired mitochondria, thus promoting CF survival and maintaining their activation.

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Section: Figure 3 | Reducing the Cardiac Fibroblasts (Cf) Glycolytic Flux May Be Important For Mitochondrial Fission Inhibition-induced Smentioning

confidence: 64%

“…Several mechanisms have been proposed to explain how CF are activated, among which metabolic reprogramming is thought to be critical. For instance, we recently demonstrated that enhanced glycolysis is crucial for CF activation (Chen et al, 2020b). Glycolysis and mitochondrial respiration are the major energy-yielding manners.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

Gao

Zhang

Tao

et al. 2021

Front. Cell Dev. Biol.

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“…Oxygen consumption rate (OCR) was measured using Seahorse XF96 (Agilent, Delaware, USA) as our previous report [28]. Briefly, cells were cultured in the working medium (Seahorse XF basal medium, Catalog, 103335-100, Agilent, Delaware, USA).…”

Section: Seahorse Analysismentioning

confidence: 99%

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

Tao

Chen

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Ketogenic diet (KD) is popular in diabetic patients but its cardiac safety and efficiency on the heart are unknown. The aim of the present study is to determine the effects and the underlined mechanisms of KD on cardiac function in diabetic cardiomyopathy (DCM). We used db/db mice to model DCM, and different diets (regular or KD) were used. Cardiac function and interstitial fibrosis were determined. T-regulatory cell (Treg) number and functions were evaluated. The effects of ketone body (KB) on fatty acid (FA) and glucose metabolism, mitochondria-associated endoplasmic reticulum membranes (MAMs), and mitochondrial respiration were assessed. The mechanisms via which KB regulated MAMs and Tregs were addressed. KD improved metabolic indices in db/db mice. However, KD impaired cardiac diastolic function and exacerbated ventricular fibrosis. Proportions of circulatory CD4+CD25+Foxp3+ cells in whole blood cells and serum levels of IL-4 and IL-10 were reduced in mice fed with KD. KB suppressed the differentiation to Tregs from naive CD4+ T cells. Cultured medium from KB-treated Tregs synergically activated cardiac fibroblasts. Meanwhile, KB inhibited Treg proliferation and productions of IL-4 and IL-10. Treg MAMs, mitochondrial respiration and respiratory complexes, and FA synthesis and oxidation were all suppressed by KB while glycolytic levels were increased. L-carnitine reversed Treg proliferation and function inhibited by KB. Proportions of ST2L+ cells in Tregs were reduced by KB, as well as the production of ST2L ligand, IL-33. Reinforcement expressions of ST2L in Tregs counteracted the reductions in MAMs, mitochondrial respiration, and Treg proliferations and productions of Treg cytokines IL-4 and IL-10. Therefore, despite the improvement of metabolic indices, KD impaired Treg expansion and function and promoted cardiac fibroblast activation and interstitial fibrosis. This could be mainly mediated by the suppression of MAMs and fatty acid metabolism inhibition via blunting IL-33/ST2L signaling.

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“…Seahorse was used to detect mitochondrial respiratory capacity as described in our previous study 52 . The Seahorse XF Cell Mito Stress Test Kit (catalog number 103015-100, Agilent, Delaware, USA) was used to directly measure the oxygen consumption rate (OCR) using an Agilent Seahorse Xfe96 Extracellular Flux Analyzer (Agilent, Delaware, USA) 53 .…”

Section: Methodsmentioning

confidence: 99%

LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity

et al. 2021

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Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep−/− mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.

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Long non-coding RNA Linc00092 inhibits cardiac fibroblast activation by altering glycolysis in an ERK-dependent manner

Cited by 20 publications

References 45 publications

RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

Ketogenic Diet Suppressed T‐Regulatory Cells and Promoted Cardiac Fibrosis via Reducing Mitochondria‐Associated Membranes and Inhibiting Mitochondrial Function

LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity

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