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

Nature Cardiovascular Research volume 4, pages 362–379 (2025)Cite this article

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Abstract

Maternal exposure to a Western-type diet (WD) increases the susceptibility of adult offspring to atherosclerosis, partly because fetal endothelial cells (ECs) become dysfunctional and inflamed due to risk factors transmitted via maternal–fetal blood exchange. However, the underlying mechanisms remain unclear. Here we show that maternal WD accelerates atherogenesis in adult offspring mice by regulating chromatin dynamics through activator protein-1 (AP-1) in aortic ECs, inducing inflammatory memory at the chromatin level. We found that 27-hydroxycholesterol is involved in memory establishment and also acts as a secondary stimulator, amplifying the expression of inflammatory factors and enhancing the enrichment of AP-1/p300 and H3K27ac in ECs. Inhibiting AP-1 binding to chromatin reduced the inflammatory response in human umbilical vein ECs from mothers with hypercholesterolemia and decreased atherogenesis in offspring mice exposed to maternal WD. Our findings demonstrate that maternal WD exacerbates EC dysfunction and atherosclerosis in adult offspring by inducing AP-1-associated epigenetic memory, which increases chromatin accessibility to inflammatory genes.

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Fig. 1: Maternal WD exacerbates atherosclerosis in offspring Ldlr−/− mice.
Fig. 2: Distinct transcriptional modules are linked to WD stimulation in MAECs.
Fig. 3: Maternal WD endows MAEC inflammation memory in offspring at the chromatin level.
Fig. 4: AP-1 TF, accompanied by H3K27ac modification, drives memory recall in MAECs.
Fig. 5: 27-HC plays a critical role in epigenetic memory establishment in vivo.
Fig. 6: 27-HC plays a critical role in epigenetic memory establishment in vitro.
Fig. 7: T-5224 blocks 27-HC-stimulated inflammatory memory in MH HUVECs.
Fig. 8: T-5224 impairs epigenetic memory and alleviates atherosclerosis.

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Data availability

High-throughput data used in this paper are available from the Gene Expression Omnibus under accession numbers GSE276350 and GSE276351. All other data supporting the findings in this study are included in the main article and associated files.

Code availability

Analyses were performed using standard R packages. No custom analysis software was created to perform these analyses. Analyses were performed using published R packages that are cited within the text and Methods sections.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81925003 and 82130014 to D.A.) and a grant from the National Key R&D Program of China (2019YFA0802502 to D.A.). Illustration items in the figures were created with BioRender.

Author information

Author notes

  1. These authors contributed equally: Kan Li, Weiqi Qian, Fangni Zhang.

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China

    Kan Li, Weiqi Qian, Fangni Zhang, Wenhui Zhang, Huizhen Lv, Meixi Quan, Weiyan Sun, Ruixin Liu & Ding Ai

  2. State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China

    Kan Li & Meng Zhang

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China

    Xinyi Cao & Yupeng Chen

  4. Experimental Research Center, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Zhong Xian, Suya Bao, Hongfeng Jiang & Jie Du

  5. State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Medicinal Chemistry and Bioinformatics Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jian Zhang

  6. Department of Gynecology and Obstetrics, Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China

    Cha Han

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Contributions

K.L., W.Q., L.S. and D.A. designed the experiments. K.L., W.Q., F.Z., W.Z., H.L., M.Q., X.C., R.L. and W.S. performed research. K.L., F.Z., W.Q. and H.J. analyzed data. K.L., Z.X., S.B. and C.H. collected the samples. M.Z., J.Z., J.D., H.J. and Y.C. oversaw the project and provided resources. K.L., W.Q., F.Z. and D.A. wrote the paper. All authors read and approved the paper.

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Correspondence to Cha Han or Ding Ai.

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Nature Cardiovascular Research thanks Philip Shaul and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Maternal WD exacerbates atherosclerosis in offspring Ldlr-/- mice.

a, Representative ultrasound images of LCA from mice were obtained on day 0 and 14 after surgery. They revealed that partial ligation induced flow reversal in LCA during diastole. b, c, IPGTT of female (b; n = 9) and male (c; n = 8) mice in each group at 8 weeks of age. d, e, Plasma levels of TG, CHO, LDL-c, and HDL-c in female (d) and male (e) mice at 8-week-old. n = 6. f, g, Plasma levels of female (f) and male (g) mice at 11-week-old. n = 6. h, IPGTT of female mice in each group at 16 weeks of age. n = 9. i, Plasma levels of female mice at 16-week-old. n = 9. j, IPGTT of male mice in each group at 16 weeks of age. n = 8. k, Plasma levels of male mice at 16-week-old. n = 9 vs. 8. Data are presented as the mean ± SEM. An unpaired two-tailed Student’s t-test was used to determine statistical significance.

Source data

Extended Data Fig. 2 Distinct transcriptional modules are linked to WD stimulation in MAECs.

a, Diagram of MAECs sorting and transcriptomic analysis (SMART-seq). b, Principal component analysis (PCA) of replicates from both CDM-CDO, WDM-CDO, CDM-WDO and WDM-WDO groups in the dataset. c, Volcano plot of differentially expressed genes (WDM-CDO vs. CDM-CDO). |log2FC|≥ 1, p.adj < 0.05, n = 3. d, Heatmap showing mRNA levels for genes within the Up (above) and Down (below) groups. e, Scaled expression of Up and Down genes in each of the four groups. f, Bubble plot showing the GO BP and KEGG pathways by analyzing the Up and Down genes in MAECs. Gene expression is depicted in violin plots, displaying maximal, minimal, median values, and the 75th and 25th percentiles(e). Ordinary one-way ANOVA with Tukey’s multiple comparison test was used to determine statistical significance. p.adj: adjusted p-value.

Source data

Extended Data Fig. 3 Maternal WD endows MAECs inflammation memory in offspring at the chromatin level.

a, Schematic figure showing the process of chromatin preparation (ATAC-seq) in MAECs. b, Genomic distribution of differential accessibility regions in MAECs from four groups. c, Multivariate correlation matrix displayed graphically. d, Heatmaps (left) showing ATAC signals for each specified peak cluster in the indicated four groups. The signal strengths are denoted by color intensities. Line graphs (right) indicating differences in chromatin accessibility between WDM-CDO vs. CDM-CDO and WDM-WDO vs. CDM-WDO groups. e, Bubble plot showing important GO BP for each module. Significance calculated by hypergeometric test for genes in different modules and adjusted by Benjamini-Hochberg method.

Source data

Extended Data Fig. 4 AP-1 TF, accompanied by H3K27ac modification, drives memory recall in MAECs.

a, Motif enrichment analysis of MAECs genomic regions in module IV/V/VI/VII. b, Relative mRNA levels of Jun in CDM and WDM mice. n = 6. c, Relative mRNA levels of Jun in CDM-CDO, WDM-CDO, CDM-WDO and WDM-WDO mice. n = 3. Data are presented as the mean ± SEM. An unpaired two-tailed Student’s t-test (b) and ordinary two-way ANOVA with Sidak’s multiple comparison test (c) were used to determine statistical significance.

Source data

Extended Data Fig. 5 27-HC plays a critical role in epigenetic memory establishment in vivo.

a, Plasma level of CHO in maternal mice just after the end of lactation. b, Plasma level of CHO in freshly weaned offspring mice. c, Relative mRNA levels of Tnf, Nlrp3 and Ccl3 in CDM and WDM mice. n = 6. d, C57BL/6 mice were subcutaneously treated with 27-OH (20 mg/kg/day) for 1 week, and CT (130 mg/kg) was subcutaneously injected daily on days 6 and 7 after 27-HC injection. Relative plasma levels of 27-HC in male C57BL/6 mice. n = 5. e, Relative plasma levels of 27-HC in maternal mice after cessation of lactation. n = 8. f, Relative plasma levels of 27-HC in female (left) and male (right) offspring mice at 3-week-old for four groups. n = 6. g, Representative images of male offspring mice arterial tissues isolated to examine atherosclerotic lesions after 3 weeks post-ligation. Scale bar, 2 mm. h, i, Representative HE staining images (h) and quantification of lesion areas (i) in ligated LCA sections. Dashed orange boxes represent LCA. n = 6. Scale bar, 100 μm. j, k, Relative plasma TNF (j) and CCL3 (k) level in CDM-WDO and WDM-WDO Ldlr-/- mice administered subcutaneously with Vec or CT. n = 6. l, Plasma levels of TG, CHO, LDL-c, and HDL-c in male mice at 11-week-old for four groups. n = 6. Data are presented as the mean ± SEM. An unpaired two-tailed Student’s t-test (a-c), ordinary one-way ANOVA with Sidak’s multiple comparison test (d), and ordinary two-way ANOVA with Sidak’s multiple comparison test (e, f, and i-l) were used to determine statistical significance.

Source data

Extended Data Fig. 6 27-HC plays a critical role in epigenetic memory establishment in vitro.

a, Relative ERα (a, left), NLRP3 (a, middle) and CCL3 (a, right) mRNA levels in HUVECs treated with siNC or siERα with or without 27-HC treatment. n = 6. b, c, CUT&RUN-qPCR analysis showing the enrichment of JUN (b) and H3K27ac (c) at NLRP3 (left) and CCL3 (right) in HUVECs treated with siNC or siERα with or without 27-HC treatment. n = 5. d, Relative NLRP3 (left) and CCL3 (right) mRNA levels in HUVECs treated with DMSO or T-5224 (20 μM) with or without 27-HC treatment. n = 6. e, f, CUT&RUN-qPCR analysis showing the enrichment of JUN (e) and H3K27ac (f) at NLRP3 (left) and CCL3 (right) in HUVECs treated with DMSO or T-5224 with or without 27-HC treatment. n = 5. Data are presented as the mean ± SEM. Ordinary two-way ANOVA with Sidak’s multiple comparison test were used to determine statistical significance.

Source data

Extended Data Fig. 7 T-5224 blocks 27-HC-stimulated inflammatory memory in MH HUVECs.

a, Relative mRNA levels of TNF, NLRP3, and CCL3 in P1 and P6 HUVECs from control pregnant patients (Ctrl; pink) and those with MH (MH; blue). n = 6. b, CUT&RUN-qPCR analyses showing the interaction of JUN with the gene bodies of 3 genes in Ctrl and MH HUVECs. n = 6. c, d, In the presence of 27-HC, CUT&RUN-qPCR analysis showing the enrichment of JUN (c) and H3K27ac (d) at TNF, NLRP3, and CCL3 in Ctrl and MH HUVECs treated with siNC or siERα. n = 5. e, Relative TNF (left) and CCL3 (right) levels by ELISA assay in Ctrl and MH HUVECs treated with DMSO or T-5224 with or without 27-HC treatment. n = 6. f, Representative western blot (above) and quantification of NLRP3 protein levels (below) in Ctrl and MH HUVECs treated with DMSO or T-5224 with or without 27-HC treatment, normalized to GAPDH. n = 6. g, Relative TNF, NLRP3, and CCL3 mRNA levels in Ctrl and MH HUVECs treated with DMSO or T-5224 with or without ox-LDL treatment. n = 6. h, CUT&RUN-qPCR analysis showing the enrichment of JUN at TNF, NLRP3, and CCL3 in Ctrl and MH HUVECs treated with DMSO or T-5224 with or without ox-LDL treatment. n = 6. i, Ctrl and MH HUVECs were subjected to 27-HC treatment for 24 hours. The lysate was immunoprecipitated with p300, followed by western blots with the indicated antibodies. n = 3. Data are presented as the mean ± SEM. Ordinary one-way ANOVA with Sidak’s multiple comparison test (a-d) and ordinary two-way ANOVA with Sidak’s multiple comparison test (e-h) were used to determine statistical significance.

Source data

Extended Data Fig. 8 T-5224 impairs epigenetic memory and alleviates atherosclerosis.

a, b, Relative plasma Tnf (a) and Ccl3 (b) level in CDM-CDO and WDM-CDO Ldlr-/- mice administered intragastrically with CMC-Na or T-5224. n = 6. c, Plasma levels of TG, CHO, LDL-c, and HDL-c in female mice at 11-week-old for four groups. n = 7. Data are presented as the mean ± SEM. Ordinary two-way ANOVA with Sidak’s multiple comparison test were used to determine statistical significance.

Extended Data Fig. 9 Mechanistic diagram of the effect of maternal high-fat diet on atherosclerosis in offspring.

a, The figure illustrates that maternal WD aggravating EC dysfunction and atherosclerosis in adult offspring acquires AP-1-associated epigenetic memory to increase chromatin accessibility of inflammatory genes, which is triggered by an elevation of 27-HC content.

Supplementary information

Supplementary Tables 1–4, (download PDF )

Supplementary Data 1 and Supplementary Fig. 1.

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Patients without or with hyperlipemia. Supplementary Table 2 Primer sequences used in qPCR. Supplementary Table 3 JUN, H3K27ac and p300 CUT&RUN–qPCR. Supplementary Table 4 Target sequences for knockdown.

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Li, K., Qian, W., Zhang, F. et al. Maternal high-fat diet exacerbates atherosclerosis development in offspring through epigenetic memory. Nat Cardiovasc Res 4, 362–379 (2025). https://doi.org/10.1038/s44161-025-00622-4

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