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Updated: Sep 3, 2026
On-Chip Endothelial Inflammatory Phenotyping
Published on: July 21, 2012
Endothelial EPAS1 as a prognostic and therapeutic target in acute myocardial infarction: integrative bioinformatics,
Xiaona Yang1, Zhongyan Li1, Lingxian Guo2
1Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
Insights
Researchers identified EPAS1 as a key regulator of ferroptosis in acute myocardial infarction (AMI). A novel endothelial pathway involving hsa-miR-138-5p/EPAS1/BACH1 was discovered, offering potential targets for cardioprotective therapies.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Genetics
Background:
- Acute myocardial infarction (AMI) is a critical cardiovascular event involving myocardial necrosis.
- Ferroptosis, a form of regulated cell death, significantly contributes to ischemic injury in AMI.
- Causal regulators of ferroptosis in AMI, especially within endothelial cells, are not well understood.
Purpose of the Study:
- To identify causal ferroptosis-related transcription factors (TFs) in AMI using integrated transcriptomics and Mendelian randomization.
- To construct a regulatory network of microRNA (miRNA), TF, and messenger RNA (mRNA) involved in ferroptosis.
- To elucidate the molecular mechanisms of this regulatory axis in endothelial cells during AMI.
Main Methods:
- Summary-data-based Mendelian randomization (SMR) and colocalization analysis were integrated with AMI transcriptomics.
- A miRNA-TF-mRNA regulatory network was built using miRNA-TF and TF-target predictions.
- TF binding site prediction, Gene Set Enrichment Analysis (GSEA), GeneMANIA, gene-disease/drug associations, phenome-wide association study (PheWAS), and RT-qPCR validation were performed.
Main Results:
- EPAS1 was identified as a causal ferroptosis-related TF in AMI (PSMR < 0.05; PHEIDI > 0.05).
- A novel endothelial-specific regulatory axis, hsa-miR-138-5p/EPAS1/BACH1, governing ferroptosis was constructed and validated in human umbilical vein endothelial cells (HUVECs).
- PheWAS indicated no significant adverse phenotypic associations for genes within this axis, suggesting potential druggability.
Conclusions:
- EPAS1 is implicated as a TF with genetic links to AMI risk.
- The identified endothelial-enriched hsa-miR-138-5p/EPAS1/BACH1 axis provides novel insights into ferroptosis regulation in AMI.
- This regulatory cascade offers potential molecular targets for developing cardioprotective strategies against ferroptosis in AMI.
Background:
Acute myocardial infarction (AMI), characterized by acute myocardial necrosis due to coronary occlusion, is a life-threatening cardiovascular event. Ferroptosis critically contributes to ischemic injury, yet its causal regulators in AMI, particularly in endothelial cells, remain elusive.
Methods:
We integrated AMI transcriptomics with summary-data-based Mendelian randomization (SMR) and colocalization to identify causal ferroptosis-related transcription factor (TF). A miRNA-TF-mRNA regulatory network was constructed via miRNA-TF and TF-target prediction. Subsequent analyses, including TF binding site prediction, GSEA, GeneMANIA, gene-disease and gene-drug association screening, phenome-wide association study (PheWAS), ROC curve evaluation, and RT-qPCR validation in HUVECs, were performed to characterize the molecular mechanisms of this axis in AMI.
Results:
EPAS1 was identified as a causal ferroptosis-related TF in AMI (P SMR < 0.05; P HEIDI > 0.05). We constructed a ferroptosis-related miRNA-TF-mRNA network and identified a novel endothelial-specific axis, hsa-miR-138-5p/EPAS1/BACH1. RT-qPCR in HUVECs validated the GEO-derived expression patterns of axis components. PheWAS further revealed no significant adverse phenotypic associations for genes within this axis, supporting the druggability of approved compounds targeting it.
Conclusion:
This study identifies EPAS1 as a TF with suggestive genetic links to AMI risk and characterizes a novel endothelial-enriched hsa-miR-138-5p/EPAS1/BACH1 regulatory axis governing ferroptosis. This molecular cascade provides candidate molecular clues for subsequent preclinical research into cardioprotective strategies targeting ferroptosis in AMI.
