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Published on: August 8, 2022
Identification and validation of pyroptosis-related genes as potential biomarkers for hypertrophic cardiomyopathy: A
Insights
This study identifies PTPN11, IRAK3, and ANXA2 as novel pyroptosis-associated biomarkers for hypertrophic cardiomyopathy (HCM). These genes offer potential insights into HCM pathogenesis and could serve as therapeutic targets for cardiovascular disease.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Cell Death Mechanisms
Background:
- Pyroptosis, a form of programmed cell death, is implicated in cardiovascular diseases.
- The specific role of pyroptosis-related genes (PRGs) in hypertrophic cardiomyopathy (HCM) remains largely uncharacterized.
- Understanding PRGs in HCM is crucial for identifying novel diagnostic markers and therapeutic strategies.
Purpose of the Study:
- To identify key pyroptosis-related gene biomarkers associated with hypertrophic cardiomyopathy (HCM).
- To explore the underlying molecular mechanisms and pathways involved in PRGs' function in HCM.
- To validate potential diagnostic markers for HCM through experimental methods.
Main Methods:
- Differential gene expression analysis using GEO2R and PRG datasets.
- Enrichment analysis (GO, KEGG) and Protein-Protein Interaction (PPI) network construction.
- Hub gene identification, TF-miRNA network analysis, and experimental validation (RT-PCR/WB).
Main Results:
- Identified 20 differentially expressed pyroptosis-related genes (DEPRGs) enriched in cytokine production and inflammatory responses.
- Key pathways involved include the Renin-angiotensin system, Adipocytokine signaling, and NF-kappa B signaling.
- Validated PTPN11 (upregulated), IRAK3 (downregulated), and ANXA2 (downregulated) as significant HCM-associated biomarkers.
Conclusions:
- PTPN11, IRAK3, and ANXA2 are identified as pyroptosis-associated biomarkers for hypertrophic cardiomyopathy (HCM).
- These biomarkers are linked to cardiac muscle contraction, HCM, fatty acid degradation, and ECM-receptor interactions.
- The findings provide potential targets for understanding HCM pathogenesis and developing new therapeutic interventions.
Abstract:
Pyroptosis plays a key role in the death of cells including cardiomyocytes, and it is associated with a variety of cardiovascular diseases. However, the role of pyroptosis-related genes (PRGs) in hypertrophic cardiomyopathy (HCM) is not well characterized. This study aimed to identify key biomarkers and explore the molecular mechanisms underlying the functions of the PRGs in HCM. The differentially expressed genes were identified by GEO2R, and the differentially expressed pyroptosis-related genes (DEPRGs) of HCM were identified by combining with PRGs. Enrichment analysis was performed using the "clusterProfiler" package of the R software. Protein-protein interactions (PPI) network analysis was performed using the STRING database, and hub genes were screened using cytoHubba. TF-miRNA coregulatory networks and protein-chemical interactions were analyzed using NetworkAnalyst. RT-PCR/WB was used for expression validation of HCM diagnostic markers. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western Blot (WB) were used to measure and compare the expression of the identified genes in the cardiac hypertrophy model and the control group. A total of 20 DEPRGs were identified, which primarily showed enrichment for the positive regulation of cytokine production, regulation of response to biotic stimulus, tumor necrosis factor production, and other biological processes. These processes primarily involved pathways related to Renin-angiotensin system, Adipocytokine signaling pathway and NF-kappa B signaling pathway. Then, a PPI network was constructed, and 8 hub genes were identified. After verification analysis, the finally identified HCM-related diagnostic markers were upregulated gene protein tyrosine phosphatase non-receptor type 11 (PTPN11), downregulated genes interleukin-1 receptor-associated kinase 3 (IRAK3), and annexin A2 (ANXA2). Further GSEA analysis revealed these 3 biomarkers primarily related to cardiac muscle contraction, hypertrophic cardiomyopathy, fatty acid degradation and ECM - receptor interaction. Moreover, we also elucidated the interaction network of these biomarkers with the miRNA network and known compounds, respectively. RT-PCR/WB results indicated that PTPN11 expression was significantly increased, and IRAK3 and ANXA2 expressions were significantly decreased in HCM. This study identified PTPN11, IRAK3, and ANXA2 as pyroptosis-associated biomarkers of HCM, with the potential to reveal the development and pathogenesis of HCM and could be potential therapeutic targets.
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