Screening and Functional Validation of Common Key Genes in Hypertrophic Cardiomyopathy and Ischemic Cardiomyopathy

Abstract

Objective

Hypertrophic cardiomyopathy (HCM) and ischemic cardiomyopathy (ICM) are the most common main etiologies of heart failure (HF), which is also a leading cause of mortality and morbidity; however, the common mechanisms triggering the gradual progression and evolution of HF have not yet been fully elucidated. Hence, the purpose of this study focuses on the communal biological mechanisms involved, screening and functional validation of common key genes.

Methods

The gene expression profiles of HCMs (GSE36961, GSE160997) and ICMs (GSE5406, GSE26887) were downloaded from the Gene Expression Omnibus (GEO) database. After the common genes (CGs) were identified based on the intersection of the differentially expressed genes (DEGs) from the GSE36961 and GSE5406 datasets, pathway enrichment, functional annotation, protein‒protein interaction (PPI) network, hub gene identification, transcription factor (TF)-mRNA regulatory network and diagnostic efficiency evaluation were performed. In addition, the hub genes were verified with the GSE160977 and GSE26887 datasets. These findings ultimately validated the functional role of Bcl6 in both cellular and animal experiments.

Results

In total, 88 CGs (54 downregulated genes and 34 upregulated genes) were screened for subsequent analyses. Functional annotation and pathway enrichment revealed the important role of angiogenesis in these two diseases. Seven important hub genes were identified, including MYC, STAT3, CEBPB, CEBPD, CDKN1A, BCL6 and MAP2K1. The TF-mRNA network revealed that BCL6, STAT3, MYC and CDKN1A were closely related and might coordinately participate in common biological pathogenesis. Receiver operating characteristic (ROC) curve analysis revealed that the hub genes had great value for clinical diagnostic efficiency. The ROC curve prediction revealed that the optimal indicator in HCM and ICM is the Bcl6 protein. Overexpression of Bcl6 ameliorates cardiac phenotypes in mouse models of both HCM and ICM.

Conclusions

Our research revealed the common potential pathogenesis mechanism of HCM and ICM. The identification of these hub genes might provide novel directions for further treatment research, clinical diagnosis and treatment.

Keywords

Genetic analysis / Hypertrophic cardiomyopathy / Ischemic cardiomyopathy / Bcl6 / Hub genes / Heart failure / HIF-1 signaling pathway

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Funding

The Youth Talent Research and Cultivation Fund of the First Affiliated Hospital of Nanchang University(YFYPY202395)

The National Natural Science Foundation of China(82400462)

Natural Science Foundation of Jiangxi Province(20242BAB21039)

Special Scientific Research Project for Talent Introduction and Training of Jiangxi Provincial Health Commission(2026Y0026)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology