Integrative Bioinformatics Analysis Revealed Mitochondrial Defects Underlying Hypoplastic Left Heart Syndrome

Diming Zhao; Yilin Liu; Zhenqiang Xu; Hechen Shen; Shanghao Chen; Shijie Zhang; Yi Li; Haizhou Zhang; Chengwei Zou; Xiaochun Ma

doi:10.2147/IJGM.S345921

Integrative Bioinformatics Analysis Revealed Mitochondrial Defects Underlying Hypoplastic Left Heart Syndrome

Int J Gen Med. 2021 Dec 14:14:9747-9760. doi: 10.2147/IJGM.S345921. eCollection 2021.

Authors

Diming Zhao¹, Yilin Liu², Zhenqiang Xu^{3

4}, Hechen Shen¹, Shanghao Chen¹, Shijie Zhang¹, Yi Li¹, Haizhou Zhang^{3

4}, Chengwei Zou^{3

4}, Xiaochun Ma^{3

4}

Affiliations

¹ Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
² Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
³ Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
⁴ Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People's Republic of China.

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.

Keywords: differential expression genes; hypoplastic left heart syndrome; integrative bioinformatics analysis; microRNAs; regulatory networks; transcription factors.

Grants and funding

This study was supported by the grants from the National Natural Science Foundation of China (81800255), the National Nature Science Foundation of Shandong Province (ZR2020MH044 to ZC) and Natural Science Foundation of Shandong Province (ZR2018BH002 to MX).