PRDM5 regulates ASK1 transcription to affect macrophage inflammation, lipid accumulation and apoptosis progression.

Background

Atherosclerotic cardiovascular disease (ASCVD) has shared genetic susceptibility across various vascular lesions. Identification of common pathogenic factors for multi-territorial atherosclerosis is urgently required. We hypothesize that PR domain zinc finger protein 5 (PRDM5) acts as a shared pathogenic regulator to facilitate systemic atherosclerotic lesions by modulating monocyte-macrophage function.

Methods

Multi-trait genome-wide association studies (GWAS) datasets were analyzed via genomic structural equation modeling (Genomic SEM) to uncover shared risk loci underlying ASCVD. Transcriptome-wide association study (TWAS) was performed in CD14+ monocytes to prioritize candidate genes. PRDM5 expression was validated in clinical peripheral blood monocytes and atherosclerotic plaques. Cellular functional assays, chromatin Immunoprecipitation quantitative real-time PCR (ChIP-qPCR), dual-luciferase reporter assay and molecular docking were combined to decipher downstream signaling and ezetimibe-mediated therapeutic effects.

Results

PRDM5 was identified as a pivotal ASCVD risk gene, with significantly upregulated expression in monocytes and plaque tissues from patients. Mechanistically, PRDM5 directly binds the ASK1 promoter to trigger ASK1/JNK/NF-κB signaling, aggravating macrophage lipid overloading, inflammatory activation and apoptosis, and further inducing endothelial dysfunction through paracrine mediators. Ezetimibe suppresses the transcriptional activity of PRDM5.

Conclusion

PRDM5 serves as a common susceptibility gene for ASCVD and facilitates macrophage pathogenic phenotypes via the ASK1/JNK/NF-κB cascade.