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Blocking H1R signal aggravates atherosclerosis by promoting inflammation and foam cell formation

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Abstract

Atherosclerosis (AS) is a chronic inflammatory arterial disease, in which abnormal lipid metabolism and foam cell formation play key roles. Histamine is a vital biogenic amine catalyzed by histidine decarboxylase (HDC) from L-histidine. Histamine H1 receptor (H1R) antagonist is a commonly encountered anti-allergic agent in the clinic. However, the role and mechanism of H1R in atherosclerosis have not been fully elucidated. Here, we explored the effect of H1R on atherosclerosis using Apolipoprotein E-knockout (ApoE−/−) mice with astemizole (AST, a long-acting H1R antagonist) treatment. The results showed that AST increased atherosclerotic plaque area and hepatic lipid accumulation in mice. The result of microarray study identified a significant change of endothelial lipase (LIPG) in CD11b+ myeloid cells derived from HDC-knockout (HDC−/−) mice compared to WT mice. Blocking H1R promoted the formation of foam cells from bone marrow-derived macrophages (BMDMs) of mice by up-regulating p38 mitogen-activated protein kinase (p38 MAPK) and LIPG signaling pathway. Taken together, these findings demonstrate that blocking H1R signal aggravates atherosclerosis by promoting abnormal lipid metabolism and macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway.

Key messages

  • Blocking H1R signal with AST aggravated atherosclerosis and increased hepatic lipid accumulation in high-fat diet (HFD)-fed ApoE−/− mice.

  • Blocking H1R signal promoted macrophage-derived foam cell formation via p38 MAPK-LIPG signaling pathway.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Weiwei Zhang, Jianguo Jia, Bingyu Li, and Sanli Qian for their contributions and technical support to this work.

Funding

The authors gratefully acknowledge the grants from the National Natural Science Foundation of China (82170258), the Science Foundation of Shanghai Committee of Science and Technology (22ZR1446700), Shanghai Sailing Program (23YF1431600), the Key Project of the Science and Technology Committee of Baoshan district of Shanghai (21-E-42), and Guangdong Basic and Applied Basic Research Foundation (2022A1515140176).

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Author notes

  1. Baoling Zhu, Yi Yang, Xiangfei Wang and Dili Sun have contributed equally to this work.

Authors and Affiliations

  1. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Baoling Zhu, Suling Ding, Yunzeng Zou & Xiangdong Yang

  2. School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Shandong, 266071, China

    Baoling Zhu

  3. Department of Medical Laboratory, College of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China

    Yi Yang

  4. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Xiangfei Wang, Dili Sun, Xiyang Yang, Xiaowei Zhu, Yunzeng Zou & Xiangdong Yang

  5. Department of Cardiology, Zhongshan Hospital Wusong Branch, Fudan University Shanghai, Shanghai, 200940, China

    Xiaowei Zhu & Xiangdong Yang

  6. Department of Cardiology, Third People’s Hospital of Huizhou, Guangdong, 516003, China

    Chun Xiao & Xiangdong Yang

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  1. Baoling Zhu
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Contributions

Xiangdong Yang, Chun Xiao and Yunzeng Zou designed the study and organized the manuscript. Baoling Zhu, Yi Yang, Xiangfei Wang and Dili Sun performed the experiments and wrote the manuscript. Xiyang Yang and Dili Sun analyzed the data and revised the manuscript. Xiaowei Zhu and Suling Ding contributed to the design of the study and the revision of the manuscript. All authors reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Chun Xiao, Yunzeng Zou or Xiangdong Yang.

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Ethics approval

All animal-related experiments in this study were carried out according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication, 8th Edition, 2011). All of experimental protocols were approved by the Committee on the Ethics of Animal Experiments of Fudan University.

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Zhu, B., Yang, Y., Wang, X. et al. Blocking H1R signal aggravates atherosclerosis by promoting inflammation and foam cell formation. J Mol Med (2024). https://doi.org/10.1007/s00109-024-02453-5

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