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Targeting ERBB2 and PIK3R1 as a therapeutic strategy for dilated cardiomyopathy: A single-cell sequencing and
Bin He1, Liping Quan1, Chengban Li1
1Graduate School of Youjiang Medical University for Nationalities, Baise, China.
Insights
This study identifies PIK3R1 and ERBB2 as drug-treatable genes in dilated cardiomyopathy (DCM). ERBB2 shows a causal link to heart failure, suggesting a protective role, while PIK3R1 correlates with immune activation in DCM.
Area of Science:
- Genomics and Bioinformatics
- Cardiovascular Research
- Oncology
Background:
- Dilated cardiomyopathy (DCM) is a major cause of heart failure.
- Current pharmaceutical options for DCM lack disease-modifying capabilities.
- Novel therapeutic targets are urgently needed for DCM treatment.
Purpose of the Study:
- To identify drug-treatable genes associated with dilated cardiomyopathy (DCM).
- To investigate the causal relationship between identified genes and heart failure.
- To explore the role of these genes in immune response and potential therapeutic interventions.
Main Methods:
- Utilized big data analysis and bioinformatics to evaluate gene sets (SC-DCM, EP-DCM, Drug).
- Employed microarray datasets to validate gene expression and discriminatory power.
- Conducted Mendelian randomization and DGIdb analysis to assess causality and identify targeted drugs.
Main Results:
- Identified PIK3R1 and ERBB2 as key drug-treatable genes in DCM.
- Confirmed a causal association between ERBB2 and heart failure; PIK3R1 showed no causal link.
- PIK3R1 correlated positively with immune activation, while ERBB2 showed negative correlation; Everolimus inhibits both.
Conclusions:
- PIK3R1 and ERBB2 are viable therapeutic targets for DCM.
- ERBB2 may protect against DCM progression to heart failure.
- Cross-expression of PIK3R1 and ERBB2 in DCM and tumors suggests shared pathways and potential for repurposed therapies.
Background:
Dilated cardiomyopathy (DCM) is widely recognized as a significant contributor to heart failure. Nevertheless, the absence of pharmaceutical interventions capable of reversing disease progression and improving prognosis underscores the imperative for additional research in this area.
Methods:
First, we identified and evaluated three gene sets, namely "SC-DCM", "EP-DCM" and "Drug", using big data and multiple bioinformatics analysis methods. Accordingly, drug-treatable ("Hub") genes in DCM were identified. Following this, four microarray expression profile datasets were employed to authenticate the expression levels and discriminatory efficacy of "Hub" genes. Additionally, mendelian randomization analysis was conducted to ascertain the causal association between the "Hub genes" and heart failure. Finally, the "DGIdb" was applied to identify "Hub" genes-targeted drugs. The "ssGSEA" algorithm assessed the level of immune cell infiltration in DCM.
Results:
Enrichment analysis showed that the "SC-DCM" and "EP-DCM" gene sets were closely associated with DCM. PIK3R1 and ERBB2 were identified as drug-treatable genes in DCM. Additional analysis using MR supported a causal relationship between ERBB2 and heart failure, but not PIK3R1. Moreover, PIK3R1 was positively correlated with immune activation, while ERBB2 was negatively correlated. We found that everolimus was a pharmacological inhibitor for both PIK3R1 and ERBB2. However, no pharmacological agonist was found for ERBB2.
Conclusion:
PIK3R1 and ERBB2 are drug-treatable genes in DCM. ERBB2 has a causal effect on heart failure, and its normal expression may play a role in preventing the progression of DCM to heart failure. In addition, there is a cross-expression of PIK3R1 and ERBB2 genes in both DCM and tumors. The adaptive immune system and PIK3R1 may be involved in DCM disease progression, while ERBB2 exerts a protective effect against DCM.
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