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.
Meng Sun, Han Sun, Hanzheng Wang et al.· Experimental Cell Research· 0 citations
Variants in
LMNA
are established causes of inherited dilated cardiomyopathy (DCM); however, the clinical significance of many rare missense variants remains uncertain. We identified the rare
LMNA
c.929 A > G (p.Gln310Arg) variant in a patient with progressive DCM and performed preliminary variant-specific functional characterization in an AC16 transient overexpression model.
Duo whole-exome sequencing and copy-number variation analysis were performed in the proband and his son. Wild-type and p.Gln310Arg lamin A expression constructs were transiently transfected into AC16 cells. Flag-tagged protein expression, Flag-based transfection efficiency, and lamin A/C distribution were assessed by western blotting and immunofluorescence staining. Mitochondrial membrane potential and intracellular ROS-associated fluorescence were assessed using JC-1 and DCFH-DA staining, respectively. ERK1/2, JNK, and p38 MAPK phosphorylation was evaluated by western blotting. Hypertrophy-associated
NPPA
and
NPPB
expression was measured by RT-qPCR, and cell area was quantified after phalloidin staining.
The
LMNA
c.929 A > G variant was classified as a variant of uncertain significance. Wild-type and p.Gln310Arg lamin A constructs showed comparable Flag-tagged protein expression and Flag-based transfection efficiency. Expression of p.Gln310Arg lamin A was associated with an increased proportion of cells displaying ring-like lamin A/C staining patterns. Variant-expressing cells showed increased intracellular DCF fluorescence, reduced JC-1 red-to-green fluorescence ratio, and selectively increased ERK1/2 phosphorylation, whereas no significant changes were detected in JNK or p38 MAPK phosphorylation. The same cells also showed a hypertrophy-like phenotype characterized by increased
NPPA
and
NPPB
expression and enlarged cell area.
In an AC16 transient overexpression model, expression of p.Gln310Arg lamin A was associated with altered lamin A/C distribution, increased intracellular ROS-associated fluorescence, reduced mitochondrial membrane potential, selectively increased ERK1/2 phosphorylation, and a hypertrophy-like cellular phenotype. These findings provide preliminary variant-specific functional evidence but do not establish the pathogenicity of the variant or the causal relationships among the observed cellular abnormalities. Further validation in endogenous and physiologically relevant cardac models is required.
Zikang Han, Yonghao Sheng, Hanice Sun et al.· Hereditas· 0 citations
