Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

HDAC3 activates endothelial NLRP3 inflammasome and promotes atherosclerosis via inhibiting the acetylation of specificity protein 1

Cell Death & Differentiation (2025)Cite this article

Subjects

Abstract

Histone deacetylase 3 (HDAC3) is an epigenetic modifying enzyme closely linked to the development of atherosclerosis. Endothelial inflammation is a critical factor in atherosclerosis. However, the role of HDAC3 in mediating epigenetic modifications and regulating endothelial inflammation in atherosclerosis remains unclear. This study aims to investigate the impact of HDAC3 on endothelial inflammation and its contribution to atherosclerosis. Firstly, single-cell transcriptomic analysis identified elevated expression of HDAC3 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in inflammatory endothelial cells of atherosclerotic plaques in symptomatic patients. Endothelial-specific knockout HDAC3 in an apolipoprotein E knockout (ApoE−/−) mice decreased atherosclerotic lesion by reducing lipid deposition and endothelial NLRP3 inflammasome activation compared with control mice. Consistently, experiments using HDAC3 inhibitor and overexpression in human umbilical vein endothelial cells (HUVECs) demonstrated that HDAC3 enhanced the transcriptional upregulation of NLRP3 inflammasome by promoting nuclear factor kappa-B pathway, thereby contributing to the activation of the NLRP3 inflammasome and cellular injury. Further studies revealed that HDAC3 reduced specificity protein 1 (SP1) Lys-703 acetylation, thereby enhancing SP1 binding to the NLRP3 promoter and promoting NLRP3 transcription. Additionally, pharmacological inhibition of HDAC3 effectively ameliorated atherosclerosis by reducing endothelial inflammation and increasing SP1 acetylation in ApoE−/− mice. Thus, these findings demonstrate a crucial role of HDAC3 in endothelial inflammation and shed light on potential therapeutic strategy for atherosclerosis via inhibition of HDAC3.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Upregulation of HDAC3 and NLRP3 expression in inflammatory endothelial cells of human atherosclerotic plaques in symptomatic patients.
Fig. 2: Deficiency of endothelial HDAC3 reduces atherosclerotic plaque formation by decreasing endothelial NLRP3 inflammasome activation.
Fig. 3: HDAC3-selective inhibitor RGFP966 suppresses NLRP3 inflammasome activation in HUVECs induced by TNF-α.
Fig. 4: Overexpression of HDAC3 aggravates NLRP3 inflammasome activation in HUVECs induced by TNF-α.
Fig. 5: HDAC3 regulates SP1 under inflammatory stimulation in HUVECs.
Fig. 6: HDAC3 regulates endothelial NLRP3 inflammasome through deacetylating SP1 in atherosclerosis.
Fig. 7: Pharmacological inhibition of HDAC3 suppresses atherosclerosis development in ApoE−/− mice.
Fig. 8: Pharmacological inhibition of HDAC3 ameliorates endothelial inflammation by enhancing SP1 acetylation in ApoE−/− mice.

Similar content being viewed by others

Data availability

The datasets generated or analyzed during the current study are available in the human carotid atherosclerotic plaques GEO database with the link: https://www.ncbi.nlm.nih.gov/geo/. The computer code, proteomics data and other data employed to generate the results, is available from the corresponding author upon reasonable request. Uncropped immunoblots are provided as Supplemental Material-Original Blots.

References

  1. Shvedunova M, Akhtar A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol. 2022;23:329–49.

    Article  CAS  PubMed  Google Scholar 

  2. Emmett MJ, Lazar MA. Integrative regulation of physiology by histone deacetylase 3. Nat Rev Mol Cell Biol. 2019;20:102–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hoeksema MA, Gijbels MJ, Van den Bossche J, van der Velden S, Sijm A, Neele AE, et al. Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol Med. 2014;6:1124–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Li X, Chen M, Chen X, He X, Li X, Wei H, et al. TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation. Eur Heart J. 2024;45:4219–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Augustin HG, Koh GY. A systems view of the vascular endothelium in health and disease. Cell. 2024;187:4833–58.

    Article  CAS  PubMed  Google Scholar 

  6. Inoue K, Kobayashi M, Yano K, Miura M, Izumi A, Mataki C, et al. Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression. Arterioscler Thromb Vasc Biol. 2006;26:2652–9.

    Article  CAS  PubMed  Google Scholar 

  7. Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, et al. Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3. J Biol Chem. 2014;289:30625–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bai Y, Du S, Li F, Huang F, Deng R, Zhou J, et al. Histone deacetylase-high mobility group box-1 pathway targeted by hypaconitine suppresses the apoptosis of endothelial cells. Exp Biol Med. 2017;242:527–35.

    Article  CAS  Google Scholar 

  9. Huang S, Chen G, Sun J, Chen Y, Wang N, Dong Y, et al. Histone deacetylase 3 inhibition alleviates type 2 diabetes mellitus-induced endothelial dysfunction via Nrf2. Cell Commun Signal. 2021;19:35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen L, Shang C, Wang B, Wang G, Jin Z, Yao F, et al. HDAC3 inhibitor suppresses endothelial-to-mesenchymal transition via modulating inflammatory response in atherosclerosis. Biochem Pharm. 2021;192:114716.

    Article  CAS  PubMed  Google Scholar 

  11. Song J, Nabeel-Shah S, Pu S, Lee H, Braunschweig U, Ni Z, et al. Regulation of alternative polyadenylation by the C2H2-zinc-finger protein Sp1. Mol Cell. 2022;82:3135–50.e9.

    Article  CAS  PubMed  Google Scholar 

  12. Sugawara A, Uruno A, Kudo M, Ikeda Y, Sato K, Taniyama Y, et al. Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Sp1 in vascular smooth muscle cells. J Biol Chem. 2002;277:9676–83.

    Article  CAS  PubMed  Google Scholar 

  13. Lee SJ, Choi EK, Seo KW, Bae JU, Kim YH, Park SY, et al. 5-Lipoxygenase plays a pivotal role in endothelial adhesion of monocytes via an increased expression of Mac-1. Cardiovasc Res. 2013;99:724–33.

    Article  CAS  PubMed  Google Scholar 

  14. Zhao J, Liu Z, Chang Z. Lipopolysaccharide induces vascular endothelial cell pyroptosis via the SP1/RCN2/ROS signaling pathway. Eur J Cell Biol. 2021;100:151164.

    Article  CAS  PubMed  Google Scholar 

  15. Tang Y, Yan JH, Ge ZW, Fei AH, Zhang YC. LncRNA Gaplinc promotes the pyroptosis of vascular endothelial cells through SP1 binding to enhance NLRP3 transcription in atherosclerosis. Cell Signal. 2022;99:110420.

    Article  CAS  PubMed  Google Scholar 

  16. Tan NY, Khachigian LM. Sp1 phosphorylation and its regulation of gene transcription. Mol Cell Biol. 2009;29:2483–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Goldberg HJ, Whiteside CI, Hart GW, Fantus IG. Posttranslational, reversible O-glycosylation is stimulated by high glucose and mediates plasminogen activator inhibitor-1 gene expression and Sp1 transcriptional activity in glomerular mesangial cells. Endocrinology. 2006;147:222–31.

    Article  CAS  PubMed  Google Scholar 

  18. Yun S, Dardik A, Haga M, Yamashita A, Yamaguchi S, Koh Y, et al. Transcription factor Sp1 phosphorylation induced by shear stress inhibits membrane type 1-matrix metalloproteinase expression in endothelium. J Biol Chem. 2002;277:34808–14.

    Article  CAS  PubMed  Google Scholar 

  19. Lu H, Jiang X, He L, Ji X, Li X, Liu S, et al. Endothelial Sp1/Sp3 are essential to the effect of captopril on blood pressure in male mice. Nat Commun. 2023;14:5891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lu H, Yuan P, Ma X, Jiang X, Liu S, Ma C, et al. Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice. Nat Commun. 2023;14:731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bashore AC, Yan H, Xue C, Zhu LY, Kim E, Mawson T, et al. High-dimensional single-cell multimodal landscape of human carotid atherosclerosis. Arterioscler Thromb Vasc Biol. 2024;44:930–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jiang LP, Yu XH, Chen JZ, Hu M, Zhang YK, Lin HL, et al. Histone deacetylase 3: a potential therapeutic target for atherosclerosis. Aging Dis. 2022;13:773–86.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang L, Chen Y, Jiang Q, Song W, Zhang L. Therapeutic potential of selective histone deacetylase 3 inhibition. Eur J Med Chem. 2019;162:534–42.

    Article  CAS  PubMed  Google Scholar 

  24. Zampetaki A, Zeng L, Margariti A, Xiao Q, Li H, Zhang Z, et al. Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow. Circulation. 2010;121:132–42.

    Article  CAS  PubMed  Google Scholar 

  25. Xiao Q, Zeng L, Zhang Z, Margariti A, Ali ZA, Channon KM, et al. Sca-1+ progenitors derived from embryonic stem cells differentiate into endothelial cells capable of vascular repair after arterial injury. Arterioscler Thromb Vasc Biol. 2006;26:2244–51.

    Article  CAS  PubMed  Google Scholar 

  26. Zeng L, Xiao Q, Margariti A, Zhang Z, Zampetaki A, Patel S, et al. HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells. J Cell Biol. 2006;174:1059–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell. 2008;30:61–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jung SB, Kim CS, Naqvi A, Yamamori T, Mattagajasingh I, Hoffman TA, et al. Histone deacetylase 3 antagonizes aspirin-stimulated endothelial nitric oxide production by reversing aspirin-induced lysine acetylation of endothelial nitric oxide synthase. Circ Res. 2010;107:877–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhuang T, Liu J, Chen X, Zhang L, Pi J, Sun H, et al. Endothelial Foxp1 suppresses atherosclerosis via modulation of Nlrp3 inflammasome activation. Circ Res. 2019;125:590–605.

    Article  CAS  PubMed  Google Scholar 

  30. McKee CM, Coll RC. NLRP3 inflammasome priming: a riddle wrapped in a mystery inside an enigma. J Leukoc Biol. 2020;108:937–52.

    Article  CAS  PubMed  Google Scholar 

  31. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lee SJ, Seo KW, Kim CD. LPS increases 5-LO expression on monocytes via an activation of Akt-Sp1/NF-κB Pathways. Korean J Physiol Pharm. 2015;19:263–8.

    Article  CAS  Google Scholar 

  34. Pazdrak K, Shi XZ, Sarna SK. TNFalpha suppresses human colonic circular smooth muscle cell contractility by SP1- and NF-kappaB-mediated induction of ICAM-1. Gastroenterology. 2004;127:1096–109.

    Article  CAS  PubMed  Google Scholar 

  35. Ishibashi H, Nakagawa K, Onimaru M, Castellanous EJ, Kaneda Y, Nakashima Y, et al. Sp1 decoy transfected to carcinoma cells suppresses the expression of vascular endothelial growth factor, transforming growth factor beta1, and tissue factor and also cell growth and invasion activities. Cancer Res. 2000;60:6531–6.

    CAS  PubMed  Google Scholar 

  36. Ye Y, Jin L, Wilmott JS, Hu WL, Yosufi B, Thorne RF, et al. PI(4,5)P2 5-phosphatase A regulates PI3K/Akt signalling and has a tumour suppressive role in human melanoma. Nat Commun. 2013;4:1508.

    Article  PubMed  Google Scholar 

  37. Luan Y, Liu H, Luan Y, Yang Y, Yang J, Ren KD. New insight in HDACs: potential therapeutic targets for the treatment of atherosclerosis. Front Pharm. 2022;13:863677.

    Article  CAS  Google Scholar 

  38. Gao Q, Wei A, Chen F, Chen X, Ding W, Ding Z, et al. Enhancing PPARγ by HDAC inhibition reduces foam cell formation and atherosclerosis in ApoE deficient mice. Pharmacol Res. 2020;160:105059.

    Article  CAS  PubMed  Google Scholar 

  39. Chi Z, Chen S, Xu T, Zhen W, Yu W, Jiang D, et al. Histone deacetylase 3 couples mitochondria to drive IL-1β-dependent inflammation by configuring fatty acid oxidation. Mol Cell. 2020;80:43–58.e7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by National Natural Science Foundation of China (No.81873520, China), Innovation Capability Support Program of Shaanxi (No.2023-CX-PT-07, China). We thank Laboratory Animal Center of Xi’an Jiaotong University for their assistance with detection of ultrasonography on mice. We thank Instrumental Analysis Center of Xi’an Jiaotong University for their help in the detection of super-resolution confocal microscope. We thank Professor Shengpeng Wang (Xi’an Jiaotong University, Xi’an, China) provides us Tie2-CreERT2 mice. We acknowledge the National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Province Center for Regenerative Medicine and Surgery Engineering Research for the laboratory and experimental platform. The graphical abstract was created with medpeer and Fig. 7A was created with FigDraw.

Author information

Authors and Affiliations

  1. Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China

    Lifang Chen, Yirong Zhang, Beibei Guo, Lan Yang, Cheng Yin, Qin Zuo, Lingxuan Ren, Liang Bai, Rong Wang, Sihai Zhao, Enqi Liu & Weirong Wang

  2. Institute of Cardiovascular Science, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

    Lifang Chen, Yirong Zhang, Beibei Guo, Lan Yang, Cheng Yin, Qin Zuo, Lingxuan Ren, Liang Bai, Rong Wang, Sihai Zhao, Enqi Liu & Weirong Wang

  3. Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Wei Zhang

  4. Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Huan Chen

Authors
  1. Lifang Chen
    View author publications

    Search author on:PubMed Google Scholar

  2. Wei Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Huan Chen
    View author publications

    Search author on:PubMed Google Scholar

  4. Yirong Zhang
    View author publications

    Search author on:PubMed Google Scholar

  5. Beibei Guo
    View author publications

    Search author on:PubMed Google Scholar

  6. Lan Yang
    View author publications

    Search author on:PubMed Google Scholar

  7. Cheng Yin
    View author publications

    Search author on:PubMed Google Scholar

  8. Qin Zuo
    View author publications

    Search author on:PubMed Google Scholar

  9. Lingxuan Ren
    View author publications

    Search author on:PubMed Google Scholar

  10. Liang Bai
    View author publications

    Search author on:PubMed Google Scholar

  11. Rong Wang
    View author publications

    Search author on:PubMed Google Scholar

  12. Sihai Zhao
    View author publications

    Search author on:PubMed Google Scholar

  13. Enqi Liu
    View author publications

    Search author on:PubMed Google Scholar

  14. Weirong Wang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

LC and WZ: Investigation, Methodology, Project administration, Writing-original draft; HC: Single-cell analysis; YZ and LR: Software; BG and LY: Formal analysis. CY and QZ: Methodology; LB, RW and SZ: Data curation; EL: Supervision; WW: Conceptualization, Funding acquisition, Writing-review & editing; All authors have read the article.

Corresponding author

Correspondence to Weirong Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

All animal experiments were approved by the Experimental Animal Ethics Committee of Xi’an Jiaotong University (2023-1534) and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, L., Zhang, W., Chen, H. et al. HDAC3 activates endothelial NLRP3 inflammasome and promotes atherosclerosis via inhibiting the acetylation of specificity protein 1. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01620-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41418-025-01620-6

Search

Advanced search

Quick links