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

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Developmental Origins of Health and Disease

Background:

• Maternal Western diet (WD) intake elevates offspring's risk for atherosclerosis.
• Endothelial cell (EC) dysfunction, driven by maternal risk factors, contributes to this susceptibility.
• The precise molecular mechanisms linking maternal diet to offspring EC dysfunction are not fully understood.

Purpose of the Study:

• To elucidate the epigenetic mechanisms by which maternal WD induces long-term EC dysfunction and accelerates atherosclerosis in adult offspring.
• To investigate the role of activator protein-1 (AP-1) and chromatin remodeling in mediating this effect.

Main Methods:

• Utilized mouse models of maternal WD exposure.
• Analyzed aortic ECs from adult offspring for inflammatory markers and epigenetic modifications.
• Investigated the role of 27-hydroxycholesterol in epigenetic memory formation.
• Assessed the impact of inhibiting AP-1 binding on EC inflammation and atherogenesis.

Main Results:

• Maternal WD induced epigenetic memory in offspring aortic ECs via AP-1 and chromatin dynamics.
• 27-hydroxycholesterol amplified inflammatory gene expression and AP-1/p300 and H3K27ac enrichment.
• Inhibiting AP-1 binding reduced inflammation in human ECs and offspring atherogenesis.

Conclusions:

• Maternal WD exacerbates offspring atherosclerosis by establishing AP-1-driven epigenetic memory in ECs.
• This epigenetic memory increases chromatin accessibility to inflammatory genes, promoting EC dysfunction.
• Targeting AP-1 offers a potential therapeutic strategy to mitigate diet-induced cardiovascular risks.