Targeting ERBB2 and PIK3R1 as a therapeutic strategy for dilated cardiomyopathy: A single-cell sequencing and mendelian randomization analysis

Bin He; Liping Quan; Chengban Li; Wei Yan; ZhuoHua Zhang; LiuFan Zhou; Qinjiang Wei; Zhile Li; Jianjiao Mo; Zhen Zhang; Xingshou Pan; JianJun Huang; Li Liu

doi:10.1016/j.heliyon.2024.e25572

Targeting ERBB2 and PIK3R1 as a therapeutic strategy for dilated cardiomyopathy: A single-cell sequencing and mendelian randomization analysis

Heliyon. 2024 Feb 13;10(5):e25572. doi: 10.1016/j.heliyon.2024.e25572. eCollection 2024 Mar 15.

Authors

Bin He¹, Liping Quan¹, Chengban Li¹, Wei Yan^{1

2}, ZhuoHua Zhang², LiuFan Zhou², Qinjiang Wei², Zhile Li², Jianjiao Mo², Zhen Zhang², Xingshou Pan², JianJun Huang^{3

4}, Li Liu^{2

5}

Affiliations

¹ Graduate School of Youjiang Medical University for Nationalities, Baise, China.
² Department of Cardiology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
³ College of Clinical Medicine, Youjiang Medical University for Nationalities, Baise, China.
⁴ Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
⁵ The Key Laboratory for High Incidence Prevention and Treatment in Guangxi Guixi Area, Baise, 533000, Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.

Abstract

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.

Keywords: Dilated cardiomyopathy; Immune cell infiltration; Mendelian randomization analysis (MR); Single-cell RNA sequencing; Weight gene co-expression network analysis (WGCNA).