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.
Highlights
Tetralogy of Fallot (TOF) is the most common cause of cyanotic congenital heart disease (CHD) and the most frequent complex CHD encountered in adulthood [1], with a prevalence of 1/3,000 births [2]
The gene set enrichment analysis (GSEA) showed that sphingolipid metabolism was downregulated in TOF and the metabolomics analysis showed that multiple sphingolipids were dysregulated
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
Summary
Tetralogy of Fallot (TOF) is the most common cause of cyanotic congenital heart disease (CHD) and the most frequent complex CHD encountered in adulthood [1], with a prevalence of 1/3,000 births [2]. The RV of patients with TOF is exposed to chronic hypoxia and hemodynamic stress [4, 5]. Chronic hypoxia affects cardiac metabolism and function [6], which causes metabolic reprogramming in CHD [7]. Metabolomics has revealed metabolic changes in the plasma or serum of patients with CHD. Cedars et al [8] reported that the amino acid metabolic pathway was significantly changed in adult CHD, which is consistent with the results of another study [9]. Tetralogy of Fallot (TOF) is the most common cyanotic heart disease. The association of cardiac metabolic reprogramming changes and underlying molecular mechanisms in TOF-related chronic myocardial hypoxia damage are still unclear
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