Integrative Bioinformatics Analysis Revealed Mitochondrial Defects Underlying Hypoplastic Left Heart Syndrome

Abstract

Background Hypoplastic left heart syndrome (HLHS) is one of the most complex congenital cardiac malformations, and the molecular mechanism of heart failure (HF) in HLHS is still elusive. Methods Integrative bioinformatics analysis was performed to unravel the underlying genes and mechanisms involved in HF in HLHS. Microarray dataset GSE23959 was screened out for the differentially expressed genes (DEGs), after which the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were carried out using the Metascape. The protein–protein interaction (PPI) network was generated, and the modules and hub genes were identified with the Cytoscape-plugin. And the integrated network of transcription factor (TF)-DEGs and miRNA-DEGs was constructed, respectively. Results A total of 210 DEGs were identified, including 135 up-regulated and 75 down-regulated genes. The functional enrichment analysis of DEGs pointed towards the mitochondrial-related biological processes, cellular components, molecular functions and signaling pathways. A PPI network was constructed including 155 nodes as well as 363 edges. And 15 hub genes, such as NDUFB6, UQCRQ, SDHD, ATP5H , were identified based on three topological analysis methods and mitochondrial components and functions were the most relevant. Furthermore, by integrating network interaction construction, 23 TFs (NFKB1, RELA, HIF1A, VHL, GATA1, PPAR-γ, etc.) as well as several miRNAs (hsa-miR-155-5p, hsa-miR-191-5p, hsa-mir-124-3p, hsa-miR-1-3p, etc.) were detected and indicated the possible involvement of NF-κB signaling pathways in mitochondrial dysfunction in HLHS. Conclusion The present study applied the integrative bioinformatics analysis and revealed the mitochondrial-related key genes, regulatory pathways, TFs and miRNAs underlying the HF in HLHS, which improved the understanding of disease mechanisms and the development of novel therapeutic targets.

Medical Therapies for Heart Failure in Hypoplastic Left Heart Syndrome

“…Although the pathophysiology of HF is complex, mitochondrial dysfunction is common across various HF etiologies [ 71 ], including HLHS [ 72 , 73 , 74 ]. Mitochondrial abnormalities include impaired mitochondrial electron transport chain (ETC) activity, increased formation of reactive oxygen species (ROS), altered metabolic substrate utilization, and aberrant mitochondrial dynamics, resulting in reduced capacity to generate myocardial adenosine trinucleotide phosphate adequate (ATP) for appropriate myocardial function reviewed in [ 71 ].…”