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Non-alcoholic fatty liver disease (NAFLD) and myocardial infarction (MI) are two major health burdens with significant prevalence and mortality. This study aimed to explore the co-expressed genes to understand the relationship between NAFLD and MI and identify potential crucial biomarkers of NAFLD-related MI using bioinformatics and machine learning. Functional enrichment analysis was conducted, a co-protein-protein interaction (PPI) network diagram was constructed, and support vector machine-recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) techniques were employed to identify one differentially expressed gene (DEG), Thrombospondin 1 (THBS1). THBS1 demonstrated strong performance in distinguishing NAFLD patients (AUC = 0.981) and MI patients (AUC = 0.900). Immuno-infiltration analysis revealed significantly lower CD8+ T cells and higher neutrophil levels in patients with NAFLD and MI. CD8+ T cells and neutrophils were effective in distinguishing NAFLD/MI from healthy controls. Correlation analysis showed that THBS1 was positively correlated with CCR (chemokine receptor), MHC class (major histocompatibility complex class), neutrophils, parainflammation, and Tfh (follicular helper T cells), and negatively correlated with CD8+ T cells, cytolytic activity, and TIL (tumor-infiltrating lymphocytes) in NAFLD and MI patients. THBS1 emerged as a novel biomarker for diagnosing NAFLD/MI in comparison to healthy controls. The results indicate that CD8+ T cells and neutrophils could serve as inflammatory immune features for differentiating patients with NAFLD/MI from healthy individuals.
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Enfermedad del Hígado Graso no Alcohólico , Trombospondina 1 , Humanos , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/genética , Máquina de Vectores de Soporte , Biomarcadores/metabolismo , Biomarcadores/análisisRESUMEN
INTRODUCTION: Acute myocardial infarction (AMI) is a serious, deadly disease with a high incidence. However, it remains unclear how necroptosis affects the pathophysiology of AMI. Using bioinformatic analyses, this study investigated necroptosis in AMI. METHODS: We obtained the GSE66360 dataset related to AMI by the GEO database. Venn diagrams were used to identify necroptosis-related differential genes (NRDEGs). The genes with differential expression in AMI were analyzed using gene set enrichment analysis, and a PPI network was established. A transcription factor prediction and enrichment analysis were conducted for the NRDEGs, and the relationships between AMI, NRDEGs, and immune cells were determined. Finally, in the additional dataset, NRDEG expression levels, immune infiltration, and ROC curve analysis were confirmed, and gene expression levels were further verified experimentally. RESULTS: GSEA revealed that necroptosis pathways were significantly enriched in AMI. We identified 10 NRDEGs, including TNF, TLR4, FTH1 and so on. Enrichment analysis indicated that the NOD-like receptor and NF-kappa B signaling pathways were significantly enriched. Four NRDEGs, FTH1, IFNGR1, STAT3, and TLR4, were identified; however, additional datasets and further experimental validation are required to confirm their roles. In addition, we determined that a high abundance of macrophages and neutrophils prompted AMI development. CONCLUSIONS: In this study, four potential genes that affect the development of AMI through necroptosis (FTH1, IFNGR1, STAT3, and TLR4) were identified. In addition, we found that a high abundance of macrophages and neutrophils affected AMI. This helps determine the pathological mechanism of necroptosis and immune cells that influence AMI and provides a novel strategy for targeted therapy.
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Biología Computacional , Infarto del Miocardio , Necroptosis , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Humanos , Necroptosis/genética , Necroptosis/fisiologíaAsunto(s)
Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Regeneración , Antígeno B7-H1/metabolismo , Antígeno B7-H1/inmunología , Animales , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Humanos , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/inmunología , Modelos Animales de Enfermedad , Infarto del Miocardio/inmunologíaRESUMEN
The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET-DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.
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Aterosclerosis , Ácidos Nucleicos Libres de Células , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Inflamasomas , Placa Aterosclerótica , Recurrencia , Accidente Cerebrovascular , Animales , Inflamasomas/metabolismo , Ratones , Masculino , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/inmunología , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/complicaciones , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/metabolismo , Ácidos Nucleicos Libres de Células/genética , Femenino , Trampas Extracelulares/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Inflamación/patología , Ratones Endogámicos C57BLRESUMEN
Post-injury dysfunction of humoral immunity accounts for infections and poor outcomes in cardiovascular diseases. Among immunoglobulins (Ig), IgA, the most abundant mucosal antibody, is produced by plasma B cells in intestinal Peyer's patches (PP) and lamina propria. Here we show that patients with stroke and myocardial ischemia (MI) had strongly reduced IgA blood levels. This was phenocopied in experimental mouse models where decreased plasma and fecal IgA were accompanied by rapid loss of IgA-producing plasma cells in PP and lamina propria. Reduced plasma IgG was detectable in patients and experimental mice 3-10 d after injury. Stroke/MI triggered the release of neutrophil extracellular traps (NETs). Depletion of neutrophils, NET degradation or blockade of NET release inhibited the loss of IgA+ cells and circulating IgA in experimental stroke and MI and in patients with stroke. Our results unveil how tissue-injury-triggered systemic NET release disrupts physiological Ig secretion and how this can be inhibited in patients.
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Trampas Extracelulares , Infarto del Miocardio , Neutrófilos , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Humanos , Animales , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Masculino , Neutrófilos/inmunología , Neutrófilos/metabolismo , Femenino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/metabolismo , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/patología , Ganglios Linfáticos Agregados/metabolismo , Inmunoglobulina A/metabolismo , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Anciano , Persona de Mediana Edad , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Inmunidad Humoral , Estudios de Casos y Controles , Ratones , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismoRESUMEN
Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.
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Inmunidad Innata , Factor 3 Regulador del Interferón , Interferón Tipo I , Infarto del Miocardio , Miocitos Cardíacos , Animales , Ratones , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/deficiencia , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Humanos , Masculino , Femenino , Fibroblastos/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Receptores CCR2/metabolismo , Receptores CCR2/deficiencia , Receptores CCR2/genética , Ratones Endogámicos C57BL , Células Endoteliales/metabolismoRESUMEN
Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.
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Interleucina-10 , Macrófagos , Ratones Endogámicos C57BL , Infarto del Miocardio , Linfocitos T Reguladores , Animales , Infarto del Miocardio/inmunología , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Linfocitos T Reguladores/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Interleucina-10/metabolismo , Interleucina-10/genética , Fenotipo , Miocardio/patología , Miocardio/inmunología , Miocardio/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/inmunología , Fibrosis , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Ratones NoqueadosRESUMEN
Background: More and more evidence supports the association between myocardial infarction (MI) and osteoarthritis (OA). The purpose of this study is to explore the shared biomarkers and pathogenesis of MI complicated with OA by systems biology. Methods: Gene expression profiles of MI and OA were downloaded from the Gene Expression Omnibus (GEO) database. The Weighted Gene Co-Expression Network Analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify the common DEGs. The shared genes related to diseases were screened by three public databases, and the protein-protein interaction (PPI) network was built. GO and KEGG enrichment analyses were performed on the two parts of the genes respectively. The hub genes were intersected and verified by Least absolute shrinkage and selection operator (LASSO) analysis, receiver operating characteristic (ROC) curves, and single-cell RNA sequencing analysis. Finally, the hub genes differentially expressed in primary cardiomyocytes and chondrocytes were verified by RT-qPCR. The immune cell infiltration analysis, subtypes analysis, and transcription factors (TFs) prediction were carried out. Results: In this study, 23 common DEGs were obtained by WGCNA and DEGs analysis. In addition, 199 common genes were acquired from three public databases by PPI. Inflammation and immunity may be the common pathogenic mechanisms, and the MAPK signaling pathway may play a key role in both disorders. DUSP1, FOS, and THBS1 were identified as shared biomarkers, which is entirely consistent with the results of single-cell RNA sequencing analysis, and furher confirmed by RT-qPCR. Immune infiltration analysis illustrated that many types of immune cells were closely associated with MI and OA. Two potential subtypes were identified in both datasets. Furthermore, FOXC1 may be the crucial TF, and the relationship of TFs-hub genes-immune cells was visualized by the Sankey diagram, which could help discover the pathogenesis between MI and OA. Conclusion: In summary, this study first revealed 3 (DUSP1, FOS, and THBS1) novel shared biomarkers and signaling pathways underlying both MI and OA. Additionally, immune cells and key TFs related to 3 hub genes were examined to further clarify the regulation mechanism. Our study provides new insights into shared molecular mechanisms between MI and OA.
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Biomarcadores , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Infarto del Miocardio , Osteoartritis , Mapas de Interacción de Proteínas , Biología de Sistemas , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Osteoartritis/genética , Osteoartritis/metabolismo , Humanos , Bases de Datos Genéticas , Transcriptoma , Condrocitos/metabolismo , Condrocitos/inmunología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Animales , Biología Computacional/métodosRESUMEN
The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at day 7 post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at day 14 post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen.NEW & NOTEWORTHY The thymus is essential for maintaining whole body T-cell output. Thymic injury can adversely affect T lymphopoiesis and T-cell immune response. This study demonstrates that MI induces thymocyte apoptosis and compromises T lymphopoiesis, resulting in fewer releases of mature thymocytes to the spleen. This process is mediated by glucocorticoids secreted by adrenal glands. Therefore, targeting glucocorticoids represents a novel approach to attenuate post-MI thymic injury.
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Adrenalectomía , Apoptosis , Linfopoyesis , Ratones Endogámicos C57BL , Infarto del Miocardio , Timo , Animales , Timo/patología , Timo/inmunología , Timo/efectos de los fármacos , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/inmunología , Infarto del Miocardio/fisiopatología , Masculino , Timocitos/metabolismo , Timocitos/patología , Timocitos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Glucocorticoides/farmacología , Eosinófilos/metabolismo , Eosinófilos/inmunología , Bazo/inmunología , Bazo/metabolismo , Bazo/patología , Modelos Animales de Enfermedad , Ratones , Corticosterona/sangreAsunto(s)
Sistema Hipotálamo-Hipofisario , Infarto del Miocardio , Sistema Hipófiso-Suprarrenal , Timo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/inmunología , Sistema Hipotálamo-Hipofisario/fisiopatología , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/inmunología , Sistema Hipófiso-Suprarrenal/fisiopatología , Humanos , Timo/inmunología , Timo/metabolismo , AnimalesRESUMEN
Introduction: Complement-mediated damage to the myocardium during acute myocardial infarction (AMI), particularly the late components of the terminal pathway (C5-convertase and C5b-9), have previously been characterized. Unfortunately, only few studies have reported a direct association between dysregulated complement activation and endothelial function. Hence, little attention has been paid to the role of the anaphylatoxin C5a. The endothelial glycocalyx (eGC) together with the cellular actin cortex provide a vasoprotective barrier against chronic vascular inflammation. Changes in their nanomechanical properties (stiffness and height) are recognized as hallmarks of endothelial dysfunction as they correlate with the bioavailability of vasoactive substances, such as nitric oxide (NO). Here, we determined how the C5a:C5aR1 axis affects the eGC and endothelial function in AMI. Methods: Samples of fifty-five patients with ST-elevation myocardial infarction (STEMI) vs. healthy controls were analyzed in this study. eGC components and C5a levels were determined via ELISA; NO levels were quantified chemiluminescence-based. Endothelial cells were stimulated with C5a or patient sera (with/without C5a-receptor1 antagonist "PMX53") and the nanomechanical properties of eGC quantified using the atomic force microscopy (AFM)-based nanoindentation technique. To measure actin cytoskeletal tension regulator activation (RhoA and Rac1) G-LISA assays were applied. Vascular inflammation was examined by quantifying monocyte-endothelium interaction via AFM-based single-cell-force spectroscopy. Results: Serum concentrations of eGC components and C5a were significantly increased during STEMI. Serum and solely C5a stimulation decreased eGC height and stiffness, indicating shedding of the eGC. C5a enhanced RhoA activation, resulting in increased cortical stiffness with subsequent reduction in NO concentrations. Monocyte adhesion to the endothelium was enhanced after both C5a and stimulation with STEMI serum. eGC degradation- and RhoA-induced cortical stiffening with subsequent endothelial dysfunction were attenuated after administering PMX53. Conclusion: This study demonstrates that dysregulated C5a activation during AMI results in eGC damage with subsequent endothelial dysfunction and reduced NO bioavailability, indicating progressively developing vascular inflammation. This could be prevented by antagonizing C5aR1, highlighting the role of the C5a:C5a-Receptor1 axis in vascular inflammation development and endothelial dysfunction in AMI, offering new therapeutic approaches for future investigations.
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Activación de Complemento , Complemento C5a , Glicocálix , Infarto del Miocardio , Receptor de Anafilatoxina C5a , Humanos , Glicocálix/metabolismo , Glicocálix/patología , Complemento C5a/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Receptor de Anafilatoxina C5a/metabolismo , Masculino , Persona de Mediana Edad , Femenino , Anciano , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Transducción de Señal , Óxido Nítrico/metabolismoRESUMEN
PURPOSE: Glycolysis and immune metabolism play important roles in acute myocardial infarction (AMI). Therefore, this study aimed to identify and experimentally validate the glycolysis-related hub genes in AMI as diagnostic biomarkers, and further explore the association between hub genes and immune infiltration. METHODS: Differentially expressed genes (DEGs) from AMI peripheral blood mononuclear cells (PBMCs) were analyzed using R software. Glycolysis-related DEGs (GRDEGs) were identified and analyzed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) for functional enrichment. A protein-protein interaction network was constructed using the STRING database and visualized using Cytoscape software. Immune infiltration analysis between patients with AMI and stable coronary artery disease (SCAD) controls was performed using CIBERSORT, and correlation analysis between GRDEGs and immune cell infiltration was performed. We also plotted nomograms and receiver operating characteristic (ROC) curves to assess the predictive accuracy of GRDEGs for AMI occurrence. Finally, key genes were experimentally validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting using PBMCs. RESULTS: A total of 132 GRDEGs and 56 GRDEGs were identified on the first day and 4-6 days after AMI, respectively. Enrichment analysis indicated that these GRDEGs were mainly clustered in the glycolysis/gluconeogenesis and metabolic pathways. Five hub genes (HK2, PFKL, PKM, G6PD, and ALDOA) were selected using the cytoHubba plugin. The link between immune cells and hub genes indicated that HK2, PFKL, PKM, and ALDOA were significantly positively correlated with monocytes and neutrophils, whereas G6PD was significantly positively correlated with neutrophils. The calibration curve, decision curve analysis, and ROC curves indicated that the five hub GRDEGs exhibited high predictive value for AMI. Furthermore, the five hub GRDEGs were validated by RT-qPCR and western blotting. CONCLUSION: We concluded that HK2, PFKL, PKM, G6PD, and ALDOA are hub GRDEGs in AMI and play important roles in AMI progression. This study provides a novel potential immunotherapeutic method for the treatment of AMI.
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Biología Computacional , Redes Reguladoras de Genes , Glucólisis , Infarto del Miocardio , Mapas de Interacción de Proteínas , Humanos , Glucólisis/genética , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Infarto del Miocardio/diagnóstico , Perfilación de la Expresión Génica , Bases de Datos Genéticas , Transcriptoma , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Valor Predictivo de las Pruebas , Masculino , Persona de Mediana Edad , Hexoquinasa/genética , Femenino , Estudios de Casos y Controles , Nomogramas , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Acute myocardial infarction (AMI) is a global health problem with high mortality. Early diagnosis can prevent the development of AMI and provide valuable information for subsequent treatment. Angiogenesis has been shown to be a critical factor in the development of infarction and targeting this process may be a potential protective strategy for preventing myocardial injury and improving the prognosis of AMI patients. This study aimed to screen and verify diagnostic markers related to angiogenesis in AMI and to investigate the molecular mechanisms of action associated with AMI in terms of immune cell infiltration. METHODS: The GSE66360 and the GSE60993 datasets were both downloaded from the GEO database and were used as the training cohort and the external validation cohort, respectively. Angiogenesis-related genes (ARGs) were downloaded from the MSigDB database. The hub ARGs were identified via LASSO, RF, and SVM-RFE algorithms. ROC curves were used to assess the accuracy of the hub ARGs. The potential mechanisms of the hub ARGs were analyzed by GSEA. The ssGSEA algorithm was used to determine differences in immune cell infiltration and immune function. The CIBERSORT algorithm was used for immune cell infiltration analysis. In addition, we constructed a ceRNA network map of differentially expressed ARGs. RESULTS: We identified the thrombomodulin (THBD) gene from ARGs as a potential diagnostic marker for AMI based on the LASSO, SVM-RFE, and RF algorithms. THBD was differentially expressed and had a potential diagnostic value (area under the curve [AUC] = 0.931 and 0.765 in the training and testing datasets, respectively). GSEA showed that the MAPK signaling pathway was more enriched in the high-expression group of THBD (P < 0.05). Immune cell infiltration analysis demonstrated that THBD was mainly positively correlated with monocytes (R = 0.48, P = 0.00055) and neutrophils (R = 0.36, P = 0.013). Finally, in the ceRNA regulatory network, THBD was closely associated with 9 miRNAs and 42 lncRNAs involved in AMI. CONCLUSION: THBD can be used as a potential diagnostic marker for AMI. This study provides new insights for future AMI diagnosis and molecular mechanism research. Moreover, immune cell infiltration plays an essential role in the occurrence and development of AMI.
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Biomarcadores , Aprendizaje Automático , Infarto del Miocardio , Trombomodulina , Humanos , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Trombomodulina/genética , Pronóstico , Bases de Datos Genéticas , Redes Reguladoras de Genes , Perfilación de la Expresión Génica , Biología ComputacionalRESUMEN
ITFG2, as an immune-modulatory intracellular protein that modulate the fate of B cells and negatively regulates mTORC1 signaling. ITFG2 is highly expressed in the heart, but its pathophysiological function in heart disease is unclear. In this study, we found that in MI mice, overexpression of ITFG2 via an AAV9 vector significantly reduced the infarct size and ameliorated cardiac function. Knockdown of endogenous ITFG2 by shRNA partially aggravated ischemia-induced cardiac dysfunction. In cardiac-specific ITFG2 transgenic (TG) mice, myocardial infarction size was smaller, eject fraction (EF) and fractional shortening (FS) was higher compared to those in wild-type (WT) mice, suggesting ITFG2 reversed cardiac dysfunction induced by MI. In hypoxic neonatal cardiomyocytes (NMCMs), overexpression of ITFG2 maintained mitochondrial function by increasing intracellular ATP production, reducing ROS levels, and preserving the mitochondrial membrane potential (MMP). Overexpression of ITFG2 reversed the mitochondrial respiratory dysfunction in NMCMs induced by hypoxia. Knockdown of endogenous ITFG2 by siRNA did the opposite. Mechanism, ITFG2 formed a complex with NEDD4-2 and ATP 5b and inhibited the binding of NEDD4-2 with ATP 5b leading to the reduction ubiquitination of ATP 5b. Our findings reveal a previously unknown ability of ITFG2 to protect the heart against ischemic injury by interacting with ATP 5b and thereby regulating mitochondrial function. ITFG2 has promise as a novel strategy for the clinical management of MI.
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Mitocondrias Cardíacas , Infarto del Miocardio , Miocitos Cardíacos , Animales , Masculino , Ratones , Células Cultivadas , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias Cardíacas/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/inmunología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
Myocardial infarction (MI) is an event of heart attack due to the formation of plaques in the interior walls of the arteries. This study is conducted to explore the role of ubiquitin-specific peptidase 47 (USP47) in cardiac function and inflammatory immunity. MI mouse models were established, followed by an appraisal of cardiac functions, infarct size, pathological changes, and USP47 and NLRP3 levels. MI cell models were established in HL-1 cells using anoxia. Levels of cardiac function-associated proteins, USP7, interferon regulatory factor 1 (IRF1), platelet factor-4 (CXCL4), pyroptotic factors, and neutrophil extracellular traps (NETs) were determined. The bindings of IRF1 to USP47 and the CXCL4 promoter and the ubiquitination of IRF1 were analyzed. USP47 was upregulated in myocardial tissues of MI mice. USP47 inhibition alleviated cardiac functions, and decreased infarct size, pro-inflammatory cytokines, NETs, NLRP3, and pyroptosis. The ubiquitination and expression levels of IRF1 were increased by silencing USP47, and IRF1 bound to the CXCL4 promoter to promote CXCL4. Overexpression of IRF1 or CXCL4 in vitro and injection of Nigericin in vivo reversed the effect of silencing USP47 on alleviating pyroptosis and cardiac functions. Collectively, USP47 stabilized IRF1 and promoted CXCL4, further promoting pyroptosis, impairing cardiac functions, and aggravating immune inflammation through NLRP3 pathways.
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Inflamasomas , Ratones Endogámicos C57BL , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Ratones , Inflamasomas/metabolismo , Masculino , Piroptosis , Factor 1 Regulador del Interferón/metabolismo , Factor 1 Regulador del Interferón/genética , Modelos Animales de Enfermedad , Línea Celular , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/genética , Factor Plaquetario 4/metabolismo , Factor Plaquetario 4/genética , Ubiquitinación , HumanosRESUMEN
Inflammation is a crucial factor in cardiac remodeling after acute myocardial infarction (MI). Neutrophils, as the first wave of leukocytes to infiltrate the injured myocardium, exacerbate inflammation and cardiac injury. However, therapies that deplete neutrophils to manage cardiac remodeling after MI have not consistently produced promising outcomes. Recent studies have revealed that neutrophils at different time points and locations may have distinct functions. Thus, transferring neutrophil phenotypes, rather than simply blocking their activities, potentially meet the needs of cardiac repair. In this review, we focus on discussing the fate, heterogeneity, functions of neutrophils, and attempt to provide a more comprehensive understanding of their roles and targeting strategies in MI. We highlight the strategies and translational potential of targeting neutrophils to limit cardiac injury to reduce morbidity and mortality from MI.
Asunto(s)
Infarto del Miocardio , Neutrófilos , Humanos , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/inmunología , Neutrófilos/inmunología , Neutrófilos/efectos de los fármacos , Animales , Miocardio/patología , Miocardio/inmunología , Miocardio/metabolismoRESUMEN
BACKGROUND: Angiogenesis has been discovered to be a critical factor in developing tumors and ischemic diseases. However, the role of angiogenesis-related genes (ARGs) in acute myocardial infarction (AMI) remains unclear. METHODS: The GSE66360 dataset was used as the training cohort, and the GSE48060 dataset was used as the external validation cohort. The random forest (RF) algorithm was used to identify the signature genes. Consensus clustering analysis was used to identify robust molecular clusters associated with angiogenesis. The ssGSEA was used to analyze the correlation between ARGs and immune cell infiltration. In addition, we constructed miRNA-gene, transcription factor network, and targeted drug network of signature genes. RT-qPCR was used to verify the expression levels of signature genes. RESULTS: Seven signature ARGs were identified based on the RF algorithm. Receiver operating characteristic curves confirmed the classification accuracy of the risk predictive model based on signature ARGs (area under the curve [AUC] = 0.9596 in the training cohort and AUC = 0.7773 in the external validation cohort). Subsequently, the ARG clusters were identified by consensus clustering. Cluster B had a more generalized high expression of ARGs and was significantly associated with immune infiltration. The miRNA and transcription factor network provided new ideas for finding potential upstream targets and biomarkers. Finally, the results of RT-qPCR were consistent with the bioinformatics analysis, further validating our results. CONCLUSIONS: Angiogenesis is closely related to AMI, and characterizing the angiogenic features of patients with AMI can help to risk-stratify patients and provide personalized treatment.
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MicroARNs , Infarto del Miocardio , Humanos , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Infarto del Miocardio/diagnóstico , MicroARNs/genética , MicroARNs/metabolismo , Neovascularización Patológica/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Masculino , Algoritmos , Análisis por Conglomerados , Femenino , AngiogénesisRESUMEN
Acute myocardial infarction (AMI), mainly triggered by vascular occlusion or thrombosis, is the most prevalent cause of morbidity and mortality among all cardiovascular diseases. The devastating consequences of AMI are further aggravated by the intricate cellular processes involved in inflammation. In the past two decades, many studies have reported that regulatory T cells (Tregs), as the main immunoregulatory cells, play a crucial role in AMI progression. This review offers a comprehensive insight into the intricate relationship between Tregs and AMI development. Moreover, it explores emerging therapeutic strategies that focus on Tregs and their exosomes. Furthermore, we underscore the importance of employing noninvasive in vivo imaging techniques to advance the clinical applications of Tregs-based treatments in AMI. Although further research is essential to fully elucidate the molecular mechanisms underlying the effects of Tregs, therapies tailored to these cells hold immense potential for the treatment of patients with AMI.
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Infarto del Miocardio , Linfocitos T Reguladores , Humanos , Linfocitos T Reguladores/inmunología , Infarto del Miocardio/inmunología , Infarto del Miocardio/terapia , Animales , Exosomas/inmunologíaRESUMEN
Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to "leukotriene production involved in inflammatory response", "lipoxygenase pathway", "metabolic pathways", and "regulation of lipolysis in adipocytes" pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.
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Metabolismo de los Lípidos , Infarto del Miocardio , Infarto del Miocardio/genética , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Metabolismo de los Lípidos/genética , Humanos , Proteínas Activadoras de la 5-Lipooxigenasa/genética , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Perfilación de la Expresión Génica , Animales , Araquidonato 5-Lipooxigenasa/genética , Araquidonato 5-Lipooxigenasa/metabolismo , Regulación de la Expresión Génica , Ratones , Masculino , Coenzima A LigasasRESUMEN
BACKGROUND: The immune system's role in ST-segment-elevated myocardial infarction (STEMI) remains poorly characterized but is an important driver of recurrent cardiovascular events. While anti-inflammatory drugs show promise in reducing recurrence risk, their broad immune system impairment may induce severe side effects. To overcome these challenges, a nuanced understanding of the immune response to STEMI is needed. METHODS: For this, we compared peripheral blood mononuclear single-cell RNA-sequencing (scRNA-seq) and plasma protein expression over time (hospital admission, 24 hours, and 6-8 weeks post-STEMI) in 38 patients and 38 controls (95â 995 diseased and 33â 878 control peripheral blood mononuclear cells). RESULTS: Compared with controls, classical monocytes were increased and CD56dim natural killer cells were decreased in patients with STEMI at admission and persisted until 24 hours post-STEMI. The largest gene expression changes were observed in monocytes, associating with changes in toll-like receptor, interferon, and interleukin signaling activity. Finally, a targeted cardiovascular biomarker panel revealed expression changes in 33/92 plasma proteins post-STEMI. Interestingly, interleukin-6R, MMP9 (matrix metalloproteinase-9), and LDLR (low-density lipoprotein receptor) were affected by coronary artery disease-associated genetic risk variation, disease status, and time post-STEMI, indicating the importance of considering these aspects when defining potential future therapies. CONCLUSIONS: Our analyses revealed the immunologic pathways disturbed by STEMI, specifying affected cell types and disease stages. Additionally, we provide insights into patients expected to benefit most from anti-inflammatory treatments by identifying the genetic variants and disease stage at which these variants affect the outcome of these (drug-targeted) pathways. These findings advance our knowledge of the immune response post-STEMI and provide guidance for future therapeutic studies.