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PROVIDER: PRJNA1303962 | ENA |
REPOSITORIES: ENA
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Project description:ALDH2/eIF3E Interaction Modulates Protein Translation Critical for Cardiomyocyte Ferroptosis in Acute Myocardial Ischemia Injury
| PRJNA1306161 | ENA
Project description:Heart disease remains the leading cause of death globally. Although reperfusion following myocardial ischemia can prevent death by restoring nutrient flow, ischemia/reperfusion injury can cause significant heart damage. The mechanisms that drive ischemia/reperfusion injury are not well understood; currently, few methods can predict the state of the cardiac muscle cell and its metabolic conditions during ischemia. Here, we explored the energetic sustainability of cardiomyocytes, using a model for cellular metabolism to predict the levels of ATP following hypoxia. We modeled glycolytic metabolism with a system of coupled ordinary differential equations describing the individual metabolic reactions within the cardiomyocyte over time. Reduced oxygen levels and ATP consumption rates were simulated to characterize metabolite responses to ischemia. By tracking biochemical species within the cell, our model enables prediction of the cell’s condition up to the moment of reperfusion. The simulations revealed a distinct transition between energetically sustainable and unsustainable ATP concentrations for various energetic demands. Our model illustrates how even low oxygen concentrations allow the cell to perform essential functions. We found that the oxygen level required for a sustainable level of ATP increases roughly linearly with the ATP consumption rate. An extracellular O2 concentration of ~0.007 mM could supply basic energy needs in non-beating cardiomyocytes, suggesting that increased collateral circulation may provide an important source of oxygen to sustain the cardiomyocyte during extended ischemia. Our model provides a time-dependent framework for studying various intervention strategies to change the outcome of reperfusion.
2024-09-02 | BIOMD0000000961 | BioModels
Project description:Myocardial ischemia–reperfusion (I/R) injury causes cardiomyocyte death and cardiac dysfunction in part through ferroptosis. Brown adipocytes (BAs) have emerged as endocrine regulators with cardioprotective potential, yet their involvement in ferroptosis modulation during I/R injury remains unclear. Here, we engineered BA sheets and transplanted them onto the ischemic myocardium in a rat I/R model to evaluate therapeutic efficacy. BA sheets transplantation significantly improved cardiac function, reduced infarct size and fibrosis, and mitigated adverse remodeling while enhancing angiogenesis. In vitro, conditioned medium derived from BA sheets promoted cardiomyocyte survival, preserved contractile performance, and inhibited apoptosis and ferroptosis under hypoxia/reoxygenation stress. Mechanistically, these effects were mediated by the activation of the NRG4–ErbB4 axis and its downstream PI3K/AKT and NRF2/HO-1 antioxidant signaling pathways. Our findings demonstrate that engineered BA sheets exert potent cardioprotection against myocardial I/R injury by suppressing ferroptosis in an NRG4–ErbB4–dependent manner, supporting their promise as a therapeutic strategy for ischemic heart disease.
2026-05-29 | GSE309984 | GEO
Project description:Cardiac injury primarily occurs in myocardial infarction with reperfusion (ischemia/reperfusion, I/R) and heart failure (HF). Once injured, the heart often fails to fully restore its function. Effective prevention strategies for cardiac injury remain limited. Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. However, the regulatory mechanisms underlying ferroptosis in cardiac injury remain unclear. We analyzed public transcriptomic data from patients with HF and found that ferroptosis was the predominant pathophysiological process underlying cardiac injury. Transcriptome RNA-seq was conducted to comprehensively understand the alterations in gene expression profiles associated with cardiomyocyte ferroptosis. We isolated neonatal rat ventricular cardiomyocytes (NRVMs) and treated them with erastin for RNA-Seq. Transcriptomic correlation analysis of cardiomyocyte ferroptosis revealed that TRIM28 had the strongest correlation with ferroptosis and was downregulated in cardiomyocyte ferroptosis. Mechanically, we identified TRIM28 as the new E3 ubiquitin ligase that mediated the degradation of IRP2 via promoting the K48 polyubiquitin chain at the K877 site of IRP2, thereby inhibiting TFR1 expression and cardiomyocyte ferroptosis. Human plasma targeted eicosanoid lipidomes data revealed that the eicosanoid metabolite 8-iso-PGF2α accumulated specifically in patients after percutaneous coronary intervention and was positively correlated with plasma levels of creatine kinase MB/cardiac troponin I. TRIM28 overexpression alleviated I/R-induced cardiac ferroptosis and 8-iso-PGF2α accumulation. Furthermore, we found that p55γ, an upstream regulator of TRIM28, interacted with TRIM28 to degrade IRP2 and downregulate TFR1, thereby suppressing ferroptosis. We demonstrated that perhexiline dually activated TRIM28 and p55γ, effectively preventing I/R-induced ferroptosis. Our results demonstrate that TRIM28 is a key suppressor of cardiomyocyte ferroptosis. The TRIM28-IRP2-TFR1 axis-mediated cardiomyocyte ferroptosis plays a crucial role in I/R injury. Collectively, these findings indicate that targeting TRIM28 represents a promising therapeutic strategy for inhibiting cardiomyocyte ferroptosis and protecting against cardiac injury.
2026-05-06 | GSE295546 | GEO
Project description:Cardiac injury primarily occurs in myocardial infarction with reperfusion (ischemia/reperfusion, I/R) and heart failure (HF). Once injured, the heart often fails to fully restore its function. Effective prevention strategies for cardiac injury remain limited. Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. However, the regulatory mechanisms underlying ferroptosis in cardiac injury remain unclear. We analyzed public transcriptomic data from patients with HF and found that ferroptosis was the predominant pathophysiological process underlying cardiac injury. Transcriptome RNA-seq was conducted to comprehensively understand the alterations in gene expression profiles associated with cardiomyocyte ferroptosis. We isolated neonatal rat ventricular cardiomyocytes (NRVMs) and treated them with erastin for RNA-Seq. Transcriptomic correlation analysis of cardiomyocyte ferroptosis revealed that TRIM28 had the strongest correlation with ferroptosis and was downregulated in cardiomyocyte ferroptosis. Mechanically, we identified TRIM28 as the new E3 ubiquitin ligase that mediated the degradation of IRP2 via promoting the K48 polyubiquitin chain at the K877 site of IRP2, thereby inhibiting TFR1 expression and cardiomyocyte ferroptosis. Human plasma targeted eicosanoid lipidomes data revealed that the eicosanoid metabolite 8-iso-PGF2α accumulated specifically in patients after percutaneous coronary intervention and was positively correlated with plasma levels of creatine kinase MB/cardiac troponin I. TRIM28 overexpression alleviated I/R-induced cardiac ferroptosis and 8-iso-PGF2α accumulation. Furthermore, we found that p55γ, an upstream regulator of TRIM28, interacted with TRIM28 to degrade IRP2 and downregulate TFR1, thereby suppressing ferroptosis. We demonstrated that perhexiline dually activated TRIM28 and p55γ, effectively preventing I/R-induced ferroptosis. Our results demonstrate that TRIM28 is a key suppressor of cardiomyocyte ferroptosis. The TRIM28-IRP2-TFR1 axis-mediated cardiomyocyte ferroptosis plays a crucial role in I/R injury. Collectively, these findings indicate that targeting TRIM28 represents a promising therapeutic strategy for inhibiting cardiomyocyte ferroptosis and protecting against cardiac injury.
2026-05-06 | GSE295525 | GEO
Project description:Cardiac injury primarily occurs in myocardial infarction with reperfusion (ischemia/reperfusion, I/R) and heart failure (HF). Once injured, the heart often fails to fully restore its function. Effective prevention strategies for cardiac injury remain limited. Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. However, the regulatory mechanisms underlying ferroptosis in cardiac injury remain unclear. We analyzed public transcriptomic data from patients with HF and found that ferroptosis was the predominant pathophysiological process underlying cardiac injury. Transcriptome RNA-seq was conducted to comprehensively understand the alterations in gene expression profiles associated with cardiomyocyte ferroptosis. We isolated neonatal rat ventricular cardiomyocytes (NRVMs) and treated them with erastin for RNA-Seq. Transcriptomic correlation analysis of cardiomyocyte ferroptosis revealed that TRIM28 had the strongest correlation with ferroptosis and was downregulated in cardiomyocyte ferroptosis. Mechanically, we identified TRIM28 as the new E3 ubiquitin ligase that mediated the degradation of IRP2 via promoting the K48 polyubiquitin chain at the K877 site of IRP2, thereby inhibiting TFR1 expression and cardiomyocyte ferroptosis. Human plasma targeted eicosanoid lipidomes data revealed that the eicosanoid metabolite 8-iso-PGF2α accumulated specifically in patients after percutaneous coronary intervention and was positively correlated with plasma levels of creatine kinase MB/cardiac troponin I. TRIM28 overexpression alleviated I/R-induced cardiac ferroptosis and 8-iso-PGF2α accumulation. Furthermore, we found that p55γ, an upstream regulator of TRIM28, interacted with TRIM28 to degrade IRP2 and downregulate TFR1, thereby suppressing ferroptosis. We demonstrated that perhexiline dually activated TRIM28 and p55γ, effectively preventing I/R-induced ferroptosis. Our results demonstrate that TRIM28 is a key suppressor of cardiomyocyte ferroptosis. The TRIM28-IRP2-TFR1 axis-mediated cardiomyocyte ferroptosis plays a crucial role in I/R injury. Collectively, these findings indicate that targeting TRIM28 represents a promising therapeutic strategy for inhibiting cardiomyocyte ferroptosis and protecting against cardiac injury.
2026-05-06 | GSE295617 | GEO
Project description:BACKGROUND: As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury, but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. Acetaldehyde dehydrogenase 2 (ALDH2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2*2), affecting around 40% of East Asians, is associated with increased risk of MI. This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI. METHODS: A Chinese cohort of 177 acute heart failure patients with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending (LAD) coronary artery ligation was conducted on wild-type, ALDH2*2, and mice with cardiomyocyte-specific knockdown of eukaryotic translation initiation factor 3 subunit E (eIF3E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry-based lipidomics and metabolomics in human plasma, mouse serum samples, mouse heart tissues, and primary cardiac myocytes. RESULTS: Human ALDH2*2 carriers exhibit more severe heart failure post-AMI with features of ferroptosis in plasma through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as Coenzyme Q10 (CoQ10) and tetrahydrobiopterin (BH4). Similar features were observed in MI mouse models of ALDH2*2, whereas ferroptosis inhibition by Fer-1 significantly improved heart functions and reversed ferroptosis markers. Importantly, ALDH2*2 significantly decreased ALDH2 protein levels, while ferroptosis-related markers, including Transferrin receptor (TFRC) and Acyl-CoA synthetase long-chain family member 4 (ACSL4), were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents the eIF3E-eIF4G1-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex through releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (e.g., TFRC, ACSL4, and UAP1) containing the GAGGACR (R: represents A/G) motif to promote ferroptosis. Consistently, cardiomyocyte-specific eIF3E knockdown restored ALDH2*2 cardiac function by attenuating ferroptosis in MI. CONCLUSIONS: ALDH2*2 aggravates acute heart failure post-MI through promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocytes ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers. Key Words: ALDH2, myocardial infarction, eIF3E, ferroptosis, protein translation
2026-03-11 | GSE305516 | GEO
Project description:Lung ischemia-reperfusion (I/R) injury is a common clinical pathology associated with high mortality. The pathophysiology of lung I/R injury involves ferroptosis and elevated protein O-GlcNAcylation levels, while the effect of O-GlcNAcylation on lung I/R injury remains unclear. This research aimed to explore the effect of O-GlcNAcylation on reducing ferroptosis in pulmonary epithelial cells caused by I/R. First, we identified O-GlcNAc transferase 1 (Ogt1) as a differentially expressed gene in lung epithelial cells of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, using single-cell sequencing, and Gene Ontology analysis (GO analysis) revealed the enrichment of the ferroptosis process. We found a time-dependent dynamic alteration in lung O-GlcNAcylation during I/R injury. Proteomics analysis identified the differentially expressed proteins enriched in ferroptosis and multiple redox-related pathways based on KEGG annotation. Thus, we generated Ogt1-conditional knockout mice and found that Ogt1 deficiency aggravated ferroptosis, as evidenced by lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), Fe2+, as well as alterations in critical protein expression glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Consistently, we found that elevated O-GlcNAcylation inhibited ferroptosis sensitivity in hypoxia/reoxygenation (H/R) injury-induced TC-1 cells via O-GlcNAcylated NF-E2-related factor-2 (Nrf2). Furthermore, both the chromatin immunoprecipitation (ChIP) assay and the dual-luciferase reporter assay indicated that Nrf2 could bind with translation start site (TSS) of glucose-6-phosphate dehydrogenase (G6PDH) and promote its transcriptional activity. As an important rate-limiting enzyme in the pentose phosphate pathway (PPP), elevated G6PDH provided a mass of nicotinamide adenine dinucleotide phosphate (NADPH) to improve the redox state of glutathione (GSH) and eventually led to ferroptosis resistance. Rescue experiments proved that Nrf2 knockdown or Nrf2-T334A (O-GlcNAcylation site) mutation abolished the protective effect of ferroptosis resistance. In summary, we revealed that O-GlcNAcylation could protect against I/R lung injury by reducing ferroptosis sensitivity via the Nrf2/G6PDH pathway. Our work will provide a new basis for clinical therapeutic strategies for pulmonary ischemia-reperfusion-induced acute lung injury.
2024-12-02 | GSE283091 | GEO
Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis.
2025-04-28 | GSE231843 | GEO
Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis.
2025-04-28 | GSE231934 | GEO