Exploring Mechanisms of Ephx2 in Treating Atherosclerosis Using Independent Cascade Model and Adverse Outcome
Caiyuzhen Zhang1, Yuanwen Dai1, Yong Chen1
1Jiangxi Normal University, 100875, China.
Background:
Atherosclerosis (AS) is a leading cause of cardiovascular diseases, characterized by lipid accumulation in arterial walls. The gene Ephx2, which encodes soluble epoxide hydrolase (sEH), is implicated in AS development, but its precise mechanisms and therapeutic potential are not fully understood.
Objectives:
This study aimed to analyze gene expression data from low-density lipoprotein receptor knockout (LDLR-/-) and LDLR-/-sEH-/- mice to identify significant genes associated with AS.
Methods:
A directed compound-protein interaction network was constructed based on these genes and related pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In the end, through resistance distance (RD) between any two nodes in this network, the Independent Cascade (IC) model was applied to explore Ephx2 mechanisms in AS, such as important Adverse Outcome Pathways (AOPs).
Results:
Several AOPs were identified as critical in AS treatment via Ephx2. The key AOPs included inflammatory response and cytokine release, cholesterol deposition and oxidation, disruption of plaque stability, smooth muscle cell proliferation and migration, and platelet activation and coagulation. Within the top AOPs of inflammatory response and cytokine release, potential target genes were identified, such as Mapk3, Pik3cd, Gnai2, Mapk10, Arnt, and RhoA. Critical paths from Ephx2 to these target genes were established, suggesting mechanisms by which Ephx2 may influence AS pathogenesis.
Conclusion:
By defining the AS network and corresponding RD, this study elucidates potential mechanisms by which Ephx2 affects AS through specific KEGG pathways, AOPs, and target genes. These findings enhanced the understanding of AS pathogenesis and highlighte potential targets like Mapk3 for developing therapeutic strategies in AS prevention and treatment.
Insights
This study reveals how the enzyme Ephx2 (soluble epoxide hydrolase) influences atherosclerosis (AS) by identifying key pathways and target genes like Mapk3. These findings offer new therapeutic targets for AS treatment.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Pharmacogenomics
Background:
- Atherosclerosis (AS) involves arterial lipid accumulation and is a major cardiovascular disease risk.
- The enzyme Ephx2 (soluble epoxide hydrolase, sEH) plays a role in AS, but its exact functions and therapeutic relevance require further investigation.
Purpose of the Study:
- To analyze gene expression in LDLR knockout mice with and without Ephx2 to find genes linked to AS.
- To construct a gene-protein interaction network and use computational models to understand Ephx2's role in AS pathogenesis.
Main Methods:
- Gene expression data analysis from LDLR knockout and LDLR/sEH double knockout mice.
- Construction of a compound-protein interaction network using KEGG pathways.
- Application of the Independent Cascade (IC) model and resistance distance (RD) to identify Adverse Outcome Pathways (AOPs) and key genes.
Main Results:
- Identification of critical AOPs in AS treatment via Ephx2, including inflammation, cholesterol metabolism, plaque stability, smooth muscle cell activity, and coagulation.
- Discovery of potential target genes within the inflammatory response pathway, such as Mapk3, PiK3cd, Gnai2, Mapk10, Arnt, and RhoA.
- Elucidation of critical pathways connecting Ephx2 to these target genes, suggesting its influence on AS development.
Conclusions:
- The study defined an AS network, revealing Ephx2's mechanisms through KEGG pathways, AOPs, and target genes.
- Enhanced understanding of AS pathogenesis and identification of Mapk3 as a potential therapeutic target for AS prevention and treatment.
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