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

Abstract

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.

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

“…Orthogonal partial least squares-discriminant analysis (OPLS-DA) and principal component analysis (PCA) were carried out using R ( 19 ). Metabolites with differential expression between two groups were identified by the variable importance in prediction (VIP) ≥ 1 ( 20 ) and | log2FC| ≥ 1 ( 4 , 21 ). From the OPLS-DA results, we extracted VIPs, and we conducted permutation test (200 permutations) to avoid over-fitting.…”

“…TOF is considered as a prototype CHD ( 2 ), which affects 3 out of 10,000 live births ( 3 ). In addition, it is the most common cause of CHD ( 4 ), which represents that 7–10% of CHD occurs in 0.5/1,000 live births ( 5 ). TOF is mainly due to the abnormal development of the arterial cone, leading to pulmonary artery stenosis, ventricular septal defect, aortic span, and finally leading to right ventricular hypertrophy ( 6 ).…”

Metabolomics: A New Tool in Our Understanding of Congenital Heart Disease

“…Combining transcriptomics and metabolomics analysis, by means of liquid chromatography coupled with mass spectrometry, on right atrial specimens in TOF patients, showed a downregulation of sphingolipids. This may reflect the chronic hypoxia experienced in many patients with TOF [ 20 ].…”