Identification of key immune-related genes in dilated cardiomyopathy using bioinformatics analysis

Li, Feng; Du, Tong-Yue; Wu, Li-Da; Zhang, Lei; Liu, Huan-Huan; Zhang, Zhen-Ye; Zhang, Jie; Zhang, Zhiyuan; Qian, Lingling; Hao, Jianfeng; Wang, Ruxing

doi:10.1038/s41598-022-26277-w

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…Myocardial fibrosis is the main pathological change in DCM, characterized by excessive proliferation of cardiac interstitial fibroblasts, collagen deposition, and abnormal distribution in the cardiac interstitium 22 . During the progression of DCM, endothelial cells injury can trigger an inflammatory response and release various chemical signaling molecules, including profibrotic factors, inflammatory cytokines, and growth factors, etc., which promote cardiac fibrosis and affect tissue repair and regeneration of the heart 23 , 24 . Additionally, endothelial cells can promote cardiac fibrosis through endothelial-to-mesenchymal transition (EndMT) 25 .…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of single-cell RNA sequencing and bulk RNA data reveals gene regulatory networks and targets in dilated cardiomyopathy

Zhang,

Niu

et al. 2024

Sci Rep

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Dilated cardiomyopathy (DCM) is a common cause of heart failure, thromboembolism, arrhythmias, and sudden cardiac death. The quality of life and long-term survival rates of patients with dilated DCM have greatly improved in recent decades. Nevertheless, the clinical prognosis for DCM patients remains unfavorable. The primary driving factors underlying the pathogenesis of DCM remain incompletely understood. The present study aimed to identify driving factors underlying the pathogenesis of DCM from the perspective of gene regulatory networks. Single-cell RNA sequencing data and bulk RNA data were obtained from the Gene Expression Omnibus (GEO) database. Differential gene analysis, single-cell genomics analysis, and functional enrichment analysis were conducted using R software. The construction of Gene Regulatory Networks was performed using Python. We used the pySCENIC method to analyze the single-cell data and identified 401 regulons. Through variance decomposition, we selected 19 regulons that showed significant responsiveness to DCM. Next, we employed the ssGSEA method to assess regulons in two bulk RNA datasets. Significant statistical differences were observed in 9 and 13 regulons in each dataset. By intersecting these differentiated regulons and identifying shared targets that appeared at least twice, we successfully pinpointed three differentially expressed targets across both datasets. In this study, we assessed and identified 19 gene regulatory networks that were responsive to the disease. Furthermore, we validated these networks using two bulk RNA datasets of DCM. The elucidation of dysregulated regulons and targets (CDKN1A, SAT1, ZFP36) enhances the molecular understanding of DCM, aiding in the development of tailored therapies for patients.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of single-cell RNA sequencing and bulk RNA data reveals gene regulatory networks and targets in dilated cardiomyopathy

Zhang,

Niu

et al. 2024

Sci Rep

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“…While T-cells, inflammatory cytokines and cytotoxic molecules have also been found in the myocardium of CCC ( 14 – 16 ), their functional characteristics and role in disease pathogenesis are poorly understood. Recent studies have explored transcriptional profiles of human left ventricular free wall heart tissue samples from CCC patients, revealing differences in DNA methylation and microRNA expression ( 17 – 20 ). However, an integrative transcriptomic approach investigating the association with immune cells and their functions is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Correlation of blood-based immune molecules with cardiac gene expression profiles reveals insights into Chagas cardiomyopathy pathogenesis

Souza-Silva,

Neves,

Koh

et al. 2024

Front. Immunol.

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IntroductionUnderstanding compartmentalized immune responses in target organs is crucial for elucidating the pathogenesis of various diseases. However, obtaining samples from affected vital organs often poses safety challenges. In this study, we aimed to investigate potential correlations between the levels of disease-associated immune molecules in the bloodstream with their gene expression profiles in the hearts of patients suffering from Chagas Cardiomyopathy (CCC). This debilitating and often fatal condition is caused by infection with the protozoan Trypanosoma cruzi.MethodsBlood samples were analyzed using the Bio-Plex platform. Gene Expression Omnibus (GEO) database was used to determine gene expression profile in heart tissue from CCC and non-Chagas controls (CTRL).ResultsElevated levels of inflammatory cytokines were detected in the plasma of CCC patients, and these levels correlated with clinical indicators of deteriorating cardiac function. Notably, 75% of the soluble factors assessed in the plasma exhibited a consistent relationship with their gene expression levels in the cardiac tissue of CCC patients. Analysis of interactions and signaling pathways related to these molecules revealed an overrepresentation of inflammatory pathways in both blood and heart compartments. Moreover, we identified that differentially expressed genes in CCC cardiac tissue were primarily associated with T-cell signaling pathways and correlated with the presence of CD8+ T cells in the myocardium.DiscussionOur findings establish a strong correlation between relevant immune molecules and their signaling pathways in both the blood and heart tissue in CCC. This validates the use of blood as a non-invasive medium for understanding immunopathology and identifying markers for cardiac dysfunction in Chagas disease.

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“…Te process of cardiomyopathy inevitably involves myocardial injury, which may lead to myocardial fbrosis, especially DCM, ultimately predisposing the heart to arrhythmias and heart failure [14]. A study employing bioinformatics analysis identifed key hub genes and associated molecules potentially highly correlated with dilated cardiomyopathy (DCM), among which four hub genes (COL3A1, COL1A2, LUM, and THBS4) showed signifcant enrichment in the fbrosis pathway [15]. In addition, cardiac remodeling, including myocardial fbrosis and likewise pathophysiological manifestations such as cardiac hypertrophy and angiogenesis, is a way of altering myocardial structure in order to compensate for cardiac insufciency, which has been signifcantly associated with the development of heart failure [16].…”

Section: Introductionmentioning

confidence: 99%

Integrative Single-Cell Analysis of Cardiomyopathy Identifies Differences in Cell Stemness and Transcriptional Regulatory Networks among Fibroblast Subpopulations

Nie,

Zhao,

Liu

et al. 2024

Cardiology Research and Practice

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Background. Cardiomyopathy encompasses a broad spectrum of diseases affecting myocardial tissue, characterized clinically by abnormalities in cardiac structure, heart failure, and/or arrhythmias. Clinically heterogeneous, major types include dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RM), ischemic cardiomyopathy (ICM), among which DCM is more prevalent, while ICM exhibits higher incidence and mortality rates. Myocardial injury during cardiomyopathy progression may lead to myocardial fibrosis. Failure to intervene early and inhibit the process of myocardial fibrosis may culminate in heart failure. Cardiac fibroblasts constitute crucial cellular components determining the extent and quality of myocardial fibrosis, with various subpopulations exerting diverse roles in cardiomyopathy progression. Despite this, understanding of the cellular plasticity and transcriptional regulatory networks of cardiac fibroblasts in cardiomyopathy remains limited. Therefore, in this study, we conducted comprehensive single-cell analysis of cardiac fibroblasts in cardiomyopathy to explore differences in cellular plasticity and transcriptional regulatory networks among fibroblast subpopulations, with the aim of providing as many useful references as possible for the diagnosis, prognosis, and treatment of cardiomyopathy. Materials and Methods. Cells with mitochondrial gene expression comprising >20% of total expressed genes were excluded. Differential expression genes (DEGs) and stemness genes within cardiac fibroblast subpopulations were subjected to Gene Ontology (GO) analysis of biological processes (BP) and AUCell analysis. Monocle software was employed to analyze the pseudo-temporal trajectory of cardiac fibroblasts in cardiomyopathy. Additionally, the Python package SCENIC was utilized to assess enrichment of transcription factors and activity of regulators within cardiac fibroblast subpopulations in cardiomyopathy. Results. Following batch effect correction, 179,927 cells were clustered into 32 clusters, designated as T_NK cells, endothelial cells, myeloid cells, fibroblasts, pericytes, SMCs, CMs, proliferating cells, EndoCs, and EPCs. Among them, 8148 fibroblasts were further subdivided into 4 subpopulations, namely C0 THBS4+ Fibroblasts, C1 LINC01133+ Fibroblasts, C2 FGF7+ Fibroblasts, and C3 AGT + Fibroblasts. Results from GO_BP and AUCell analyses suggest that C3 AGT + Fibroblasts may be associated with immune response activation, protein transport, and myocardial contractile function, correlating with disease progression in cardiomyopathy. Transcription factor enrichment analysis indicates that FOS is the most significant TF in C3 AGT + Fibroblasts, also associated with the M1 module, possibly implicated in protein hydrolysis, intracellular DNA replication, and cell proliferation. Moreover, correlation analysis of transcriptional regulatory activity between fibroblast subpopulations reveals a more pronounced heterogeneity within C3 AGT + Fibroblasts in cardiomyopathy. Conclusion. C3 AGT + Fibroblasts exhibit increased sensitivity towards adverse outcomes in cardiomyopathy, such as myocardial fibrosis and impaired cardiac contractile function, compared to other cardiac fibroblast subpopulations. The differential cellular plasticity and transcriptional regulatory activity between C3 AGT + Fibroblasts and other subgroups offer new perspectives for targeting fibroblast subpopulation activity to treat cardiomyopathy. Additionally, stemness genes EPAS1 and MYC, along with the regulator FOS, may play roles in modulating the biological processes of cardiac fibroblasts in cardiomyopathy.

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Identification of key immune-related genes in dilated cardiomyopathy using bioinformatics analysis

Cited by 7 publications

References 29 publications

Integrated analysis of single-cell RNA sequencing and bulk RNA data reveals gene regulatory networks and targets in dilated cardiomyopathy

Integrated analysis of single-cell RNA sequencing and bulk RNA data reveals gene regulatory networks and targets in dilated cardiomyopathy

Correlation of blood-based immune molecules with cardiac gene expression profiles reveals insights into Chagas cardiomyopathy pathogenesis

Integrative Single-Cell Analysis of Cardiomyopathy Identifies Differences in Cell Stemness and Transcriptional Regulatory Networks among Fibroblast Subpopulations

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