Maternal high-fat diet exacerbates atherosclerosis development in offspring through epigenetic memory.

Summary

Using mouse models and human endothelial cells, the study shows that maternal Western-type diet imprints an AP-1/p300–H3K27ac epigenetic program in aortic endothelium, creating inflammatory memory that accelerates offspring atherogenesis. 27-hydroxycholesterol contributes to memory establishment and acts as a secondary amplifier; blocking AP-1–chromatin binding dampens endothelial inflammation and reduces atherosclerosis.

Key Findings

• Maternal Western-type diet accelerates offspring atherogenesis by inducing AP-1–driven inflammatory chromatin memory in aortic endothelial cells.
• 27-hydroxycholesterol participates in memory establishment and acts as a secondary stimulator, enhancing AP-1/p300 and H3K27ac enrichment.
• Pharmacologic inhibition of AP-1–chromatin binding reduces endothelial inflammatory responses and decreases atherosclerosis in offspring exposed to maternal WD.

Clinical Implications

Strengthens rationale for preconception/prenatal cardiometabolic optimization and suggests translational avenues (AP-1 pathway modulators, oxysterol signaling) to mitigate programmed vascular risk.

Limitations

• Preclinical murine model; human causal validation and dose–response extrapolation are pending
• Specific dietary composition and exposure windows may limit generalizability

Future Directions

Test AP-1/oxysterol pathway modulators in translational models; define critical gestational windows; evaluate reversibility via maternal lifestyle interventions.