Transcriptome analysis defines myocardium gene signatures in children with ToF and ASD and reveals disease-specific molecular reprogramming in response to surgery with cardiopulmonary bypass

Front. Cardiovasc. Med.

Huang²,

Yao³

et al. 2023

BackgroundTetralogy of Fallot (TOF) belongs to cyanotic heart damage, which is the most common in clinic. In the chronic myocardial hypoxia injury related to TOF, the potential molecular mechanism of cardiac energy metabolism remains unclear.Materials and methodsIn our study, microarray transcriptome analysis and metabonomics methods were used to explore the energy metabolism pathway during chronic hypoxia injury. The gene expression omnibus (GEO) dataset GSE132176 was obtained for analyzing the metabolic pathways. The clinical samples (right atrial tissues) of atrial septal defect (ASD) and TOF were analyzed by metabonomics. Next, we screened important pathways and important differential metabolites related to energy metabolism to explore the pathogenesis of TOF.ResultsGene set enrichment analysis (GSEA) indicated that fructose 6-phosphate metabolic process, triglyceride metabolic process, and et al. were significantly enriched. Gene set variation analysis (GSVA) results showed that significant difference of ASD group and TOF group existed in terpenoid metabolic process and positive regulation of triglyceride metabolic process. Pathways with significant enrichment (impact > 0.1) in TOF were caffeine metabolism (impact = 0.69), sphingolipid metabolism (impact = 0.46), glycerophospholipid metabolism (impact = 0.26), tryptophan metabolism (impact = 0.24), galactose metabolism (impact = 0.11). Pathways with significant enrichment (impact > 0.1) in ASD are caffeine metabolism (impact = 0.69), riboflavin metabolism (impact = 0.5), alanine, aspartate and glutamate metabolism (impact = 0.35), histidine metabolism (impact = 0.34) and et al.ConclusionDisturbed energy metabolism occurs in patients with TOF or ASD, and further investigation was needed to further clarify mechanism.

Section: Methodsmentioning

confidence: 99%

Energy metabolism disorder dictates chronic hypoxia damage in heart defect with tetralogy of fallot

Front. Cardiovasc. Med.

Huang²,

Yao³

et al. 2023

“…High-throughput datasets GSE132176 ( 12 ) and GSE141955 ( 13 ) were downloaded from the Gene Expression Omnibus ( https://www.ncbi.nlm.nih.gov/geo ). GSE132176 contains RA biopsies from 10 patients with TOF and 10 patients with ASD before [precardiopulmonary bypass (CPB)] and after (post-CPB) CPB surgery.…”

Section: Methodsmentioning

confidence: 99%

Circular Network of Coregulated Sphingolipids Dictates Chronic Hypoxia Damage in Patients With Tetralogy of Fallot

Zhou

Front. Cardiovasc. Med.

Zou

et al. 2022

Background: Tetralogy of Fallot (TOF) is the most common cyanotic heart disease. However, the association of cardiac metabolic reprogramming changes and underlying molecular mechanisms in TOF-related chronic myocardial hypoxia damage are still unclear.Methods: In this study, we combined microarray transcriptomics analysis with liquid chromatography tandem-mass spectrometry (LC–MS/MS) spectrum metabolomics analysis to establish the metabolic reprogramming that occurs in response to chronic hypoxia damage. Two Gene Expression Omnibus (GEO) datasets, GSE132176 and GSE141955, were downloaded to analyze the metabolic pathway in TOF. Then, a metabolomics analysis of the clinical samples (right atrial tissue and plasma) was performed. Additionally, an association analysis between differential metabolites and clinical phenotypes was performed. Next, four key genes related to sphingomyelin metabolism were screened and their expression was validated by real-time quantitative PCR (QT-PCR).Results: The gene set enrichment analysis (GSEA) showed that sphingolipid metabolism was downregulated in TOF and the metabolomics analysis showed that multiple sphingolipids were dysregulated. Additionally, genes related to sphingomyelin metabolism were identified. We found that four core genes, UDP-Glucose Ceramide Glucosyltransferase (UGCG), Sphingosine-1-Phosphate Phosphatase 2 (SGPP2), Fatty Acid 2-Hydroxylase (FA2H), and Sphingosine-1-Phosphate Phosphatase 1 (SGPP1), were downregulated in TOF.Conclusion: Sphingolipid metabolism was downregulated in TOF; however, the detailed mechanism needs further investigation.

“…The GSE132176 dataset ( 27 ) is based on the GPL13158 Affymetrix HT HG-U133+ PM Array Plate platform [HT_HG-U133_Plus_PM] and includes 40 biopsy specimens of right atrial pre-CPB (CPB_before) and post-CPB (CPB_after) from 10 patients with tetralogy of Fallot (TOF) and 10 patients with atrial septal defect (ASD). The GSE132176 dataset was used as a training set to construct co-expression networks to screen for modules closely related to post-CPB.…”

Section: Methodsmentioning

confidence: 99%

Weighted gene co-expression identification of CDKN1A as a hub inflammation gene following cardiopulmonary bypass in children with congenital heart disease

Chen

et al. 2022

Front. Surg.

BackgroundCongenital heart disease (CHD) is the most common type of birth defect. Most patients with CHD require surgery, and cardiopulmonary bypass (CPB) is the most common surgery performed.MethodsThe present study utilized weighted gene co-expression network analysis (WGCNA) to identify key inflammation genes after CPB for CHD. The GSE132176 dataset was downloaded from the Gene Expression Omnibus(GEO) database for WGCNA to identify the modules closely related to clinical traits. Disease enrichment, functional annotation and pathway enrichment were performed on genes in the module closely related to clinical traits using Enrichr and Metascape. Immune infiltration analysis was also performed on the training dataset using CIBERSORT. Finally, we identified hub genes using high gene significance (GS), high module members (MMs) and Cytoscape, and we verified the hub genes using an independent dataset and Western blot analysis.ResultsWGCNA showed that the brown module with 461 genes had the highest correlation to CHD after CPB. Functional annotation and pathway enrichment analysis were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, which showed that genes in the brown module were enriched in inflammation-related pathways. In the disease enrichment analysis, genes in the brown module were enriched for inflammatory diseases. After the 30 most highly associated brown intramodular genes were screened, a protein-protein interaction network was constructed using the STRING online analysis website. The protein-protein interaction results were then calculated using 12 algorithms in the cytoHubba plugin of Cytoscape software. The final result showed that CDKN1A was the fundamental gene of post-CPB for CHD. Using another independent validation dataset (GSE12486), we confirmed that CDKN1A was significantly differentially expressed between preoperative and postoperative CPB (Wilcoxon, P = 0.0079; T-test, P = 0.006). In addition, CDKN1A expression was elevated in eosinophils, neutrophils, memory CD4 T cells and activated mast cells. Western blot analysis showed that the expression of CDKN1A protein was significantly higher postoperative CPB than preoperative CPB. Moreover, CDKN1A was mainly related to inflammation.ConclusionIn summary, we found a relationship between CDKN1A and inflammation after CPB for congenital heart disease by WGCNA, experiments and various bioinformatics methods. Thus, CDKN1A maybe serve as a biomarker or therapeutic target for accurate diagnosis and treatment of inflammation after CPB in the future.