Exploring Dysregulated Ferroptosis-Related Genes in Septic Myocardial Injury Based on Human Heart Transcriptomes: Evidence and New Insights

Zou, Hua-Xi; Hu, Tie; Zhao, Jun; Qiu, Bai‐Quan; Zou, Chen-Chao; Xu, Qiang; Liu, Jichun; Lai, Songqing; Huang, Huang

doi:10.2147/jir.s400107

Cited by 5 publications

(4 citation statements)

References 89 publications

(115 reference statements)

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“…Altered transcriptome in ICM is associated with the dysregulation of genes related to ferroptosis. GSEA is a widely-utilized method for evaluating the pertinence of defined gene sets with respect to the disease phenotype in disease transcriptomes (36). GSEA was used to assess the variation of FRGs in the transcriptome of individuals with ICM vs. the control group, as presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis‑related genes

Zhao,

Qiu,

Zeng

et al. 2024

Exp Ther Med

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Ischemic cardiomyopathy (ICM) is a serious cardiac disease with a very high mortality rate worldwide, which causes myocardial ischemia and hypoxia as the main damage. Further understanding of the underlying pathological processes of cardiomyocyte injury is key to the development of cardioprotective strategies. Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid hydroperoxides to lethal levels, resulting in oxidative damage to the cell membrane. The current understanding of the role and regulation of ferroptosis in ICM is still limited, especially in the absence of evidence from large-scale transcriptomic data. Through comprehensive bioinformatics analysis of human ICM transcriptome data obtained from the Gene Expression Omnibus database, the present study identified differentially expressed ferroptosis-related genes (DEFRGs) in ICM. Subsequently, their potential biological mechanisms and cross-talk were analyzed, and hub genes were identified by constructing protein-protein interaction networks. Ferroptosis features such as reactive oxygen species generation, changes in ferroptosis marker proteins, iron ion aggregation and lipid oxidation, were identified in the H9c2 anoxic reoxygenation injury model. Finally, the diagnostic ability of Gap junction alpha-1 (GJA1), Solute carrier family 40 member 1 (SLC40A1), Alpha-synuclein (SNCA) were identified through receiver operating characteristic curves and the expression of DEFRGs was verified in an in vitro model. Furthermore, potential drugs (retinoic acid) that could regulate ICM ferroptosis were predicted based on key DEFRGs. The present article presents new insights into the role of ferroptosis in ICM, investigating the regulatory role of ferroptosis in the pathological process of ICM and advocating for ferroptosis as a potential novel therapeutic target for ICM based on evidence from the ICM transcriptome.

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Section: Resultsmentioning

confidence: 99%

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis‑related genes

Zhao,

Qiu,

Zeng

et al. 2024

Exp Ther Med

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“…NOX4-and Tf/TfR-mediated peroxidation and iron overload exacerbate neuronal ferroptosis after intracerebral hemorrhage (58). In septic myocardial injury, NOX4 has been identified as a key ferroptosis-related gene that regulate ferroptosis (24). As shown in this study, GDF11 overexpression inhibited ferroptosis in lung tissue of septic mice and HPMVECs challenged with LPS.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation (23). In septic myocardial injury, NOX4 has been identified as a key ferroptosis-related gene that regulate ferroptosis (24). Therefore, we hypothesized that GDF11 could alleviate sepsis-induced lung microvascular endothelial barrier damage by activating SIRT1 to inhibit NOX4-mediated ferroptosis.…”

Section: Introductionmentioning

confidence: 99%

Gdf11 Overexpression Alleviates Sepsis-Induced Lung Microvascular Endothelial Barrier Damage by Activating Sirt1/Nox4 Signaling to Inhibit Ferroptosis

Wu,

Xi,

Zhao

et al. 2024

Shock

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Sepsis is a lethal clinical syndrome, and acute lung injury (ALI) is the earliest and most serious complication. We aimed to explore the role of growth differentiation factor 11 (GDF11) in sepsis-induced dysfunction of lung microvascular endothelial barrier in vivo and in vitro to elucidate its potential mechanism related to sirtuin 1 (SIRT1)/NADPH oxidase 4 (NOX4) signaling. Cecal ligation and puncture (CLP)-induced sepsis mice and lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cells (PMECs) were use in this study. Histopathological changes in lung tissues were tested by H&E staining. Lung wet-to-dry weight ratio and inflammatory factors contents in bronchoalveolar lavage fluid (BALF) were assessed. Evens blue index, TEER and expression of zona occludens 1 (ZO-1), occludin-1 and Claudin-1 were used to evaluate alveolar barrier integrity. Reactive oxygen species (ROS), lipid peroxidation and ferroptosis markers were analyzed. Iron deposition in the lung tissues was assessed using Prussian blue staining. Intracellular Fe2+ level was detected using FerroOrange staining. Additionally, expression of GDF11, SIRT1 and NOX4 was estimated with western blot. Then, EX527, a SIRT1 inhibitor, was employed to treat GDF11-overexpressed PMECs with LPS stimulation to clarify the regulatory mechanism. Results showed that GDF11 overexpression attenuated sepsis-induced pathological changes and inflammation and maintained alveolar barrier integrity. Moreover, GDF11 overexpression inhibited ferroptosis, upregulated SIRT1 expression and downregulated NOX4 expression. Additionally, EX527 treatment relieved the impacts of GDF11 overexpression on ferroptosis and destruction of integrity of HPMVECs exposed to LPS. Taken together, GDF11 overexpression could alleviate sepsis-induced lung microvascular endothelial barrier damage by activating SIRT1/NOX4 signaling to inhibit ferroptosis. Our findings potentially provide new molecular target for clinical therapy of ALI.

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“…Microarrays have been used to screen for differential miRNAs and mRNAs involved in diseases such as cancer [15] , sepsis, and acute kidney injury [16] . Previous studies have also reported differentially expressed genes (DEGs) in patients with septic myocardial injury via microarray microarrays [17] . Therefore, it is feasible to investigate the molecular pathways involved in septic myocardial injury via the use of microarrays.…”

Section: Introductionmentioning

confidence: 99%

miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2

Jiang,

Xu,

Zeng

et al. 2024

ABBS

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Myocardial damage is a critical complication and a significant contributor to mortality in sepsis. MicroRNAs (miRNAs) have emerged as key players in sepsis pathogenesis. In this study, we explore the effect and mechanisms of miR-29b-1-5p on sepsis-induced myocardial damage. Sepsis-associated Gene Expression Omnibus datasets (GSE72380 and GSE29914) are examined for differential miRNAs. The mouse sepsis-induced cardiac injury was established by Lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). LPS-treated HL-1 mouse cardiomyocytes simulate myocardial injury in vitro . miR-29b-1-5p is co-upregulated in both datasets and in cardiac tissue from sepsis mouse and HL-1 cell models. miR-29b-1-5p expression downregulation was achieved by antagomir transduction and confirmed by real-time quantitative reverse transcription PCR. Survival analysis and echocardiography examination show that miR-29b-1-5p inhibition improves mice survival cardiac function in LPS- and CLP-induced sepsis mice. Hematoxylin and eosin and Masson’s trichrome staining and Immunohistochemistry analysis of mouse myocardial α-smooth muscle actin show that miR-29b-1-5p inhibition reduces myocardial tissue injury and fibrosis. The inflammatory cytokines and cardiac troponin I (cTnI) levels in mouse serum and HL-1 cells are also decreased by miR-29b-1-5p inhibition, as revealed by enzyme-linked immunosorbent assay. The expressions of autophagy-lysosomal pathway-related and apoptosis-related proteins in the mouse cardiac tissues and HL-1 cells are evaluated by western blot analysis. The sepsis-induced activation of the autophagy-lysosomal pathway and apoptosis are also reversed by miR-29b-1-5p antagomir. MTT and flow cytometry measurement further confirm the protective role of miR-29b-1-5p antagomir in HL-1 cells by increasing cell viability and suppressing cell apoptosis. Metascape functionally enriches TargetScan-predicted miR-29b-1-5p target genes. TargetScan prediction and dual luciferase assay validate the targeting relationship between miR-29b-1-5p and telomeric repeat-binding factor 2 (TERF2). The expression and function of TERF2 in HL-1 cells and mice are also evaluated. MiR-29b-1-5p negatively regulates the target gene TERF2 . TERF2 knockdown partly restores miR-29b-1-5p antagomir function in LPS-stimulated HL-1 cells. In summary, miR-29b-1-5p targetedly inhibits TERF2, thereby enhancing sepsis-induced myocardial injury.

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Exploring Dysregulated Ferroptosis-Related Genes in Septic Myocardial Injury Based on Human Heart Transcriptomes: Evidence and New Insights

Cited by 5 publications

References 89 publications

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis‑related genes

Exploring the molecular biology of ischemic cardiomyopathy based on ferroptosis‑related genes

Gdf11 Overexpression Alleviates Sepsis-Induced Lung Microvascular Endothelial Barrier Damage by Activating Sirt1/Nox4 Signaling to Inhibit Ferroptosis

miR-29b-1-5p exacerbates myocardial injury induced by sepsis in a mouse model by targeting TERF2

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