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Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction

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Abstract

Myocardial infarction (MI) is a significant contributor to the development of heart failure. Histidine decarboxylase (HDC), the unique enzyme that converts l-histidine to histamine, is highly expressed in CD11b+ immature myeloid cells. However, the relationship between HDC-expressing macrophages and cardiac myofibroblasts remains to be explained. Here, we demonstrate that the GFP (green fluorescent protein)-labeled HDC+CD11b+ myeloid precursors and their descendants could differentiate into fibroblast-like cells in myocardial interstitium. Furthermore, we prove that CD11b+Ly6C+ monocytes/macrophages, but not CD11b+Ly6G+ granulocytes, are identified as the main cellular source for bone marrow-derived myofibroblast transformation, which could be regulated via histamine H1 and H2 receptor-dependent signaling pathways. Using HDC knockout mice, we find that histamine deficiency promotes myofibroblast transformation from Ly6C+ macrophages and cardiac fibrosis partly through upregulating the expression of Krüppel-like factor 5 (KLF5). Taken together, our data uncover a central role of HDC in regulating bone marrow-derived macrophage-to-myofibroblast transformation but also identify a histamine receptor (HR)-KLF5 related signaling pathway that mediates myocardial fibrosis post-MI.

Graphical abstract

CD11b+Ly6C+ monocytes/macrophages are the main cellular source for bone marrow-derived myofibroblast transformation. Histamine inhibits myofibroblasts transformation via H1R and H2R-dependent signaling pathways, and ameliorates cardiac fibrosis partly through upregulating KLF5 expression.

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Abbreviations

α-SMA:

Alpha smooth muscle actin

GFP:

Green fluorescent protein

HA:

Histamine

HDC:

Histidine decarboxylase

H1R:

Histamine type 1 receptor

H2R:

Histamine type 2 receptor

IL-13:

Interleukin-13

KLF4:

Krüppel-like factor 4

KLF5:

Krüppel-like factor 5

M-CSF:

Macrophage colony stimulating factor

MI:

Myocardial infarction

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Acknowledgements

We gratefully acknowledge Long Deng, Jinmiao Chen, Hui Li, Zheliang Zhou, Zhiwei Zhang, Jianguo Jia, Bingyu Li, and Sanli Qian for their excellent technical assistance and kind suggestions.

Funding

This work was supported by the National Key Research and Development Plan (2016YFC1101102), the National Natural Science Foundation of China (81521001, 82170258), the Basic Research Project of Shanghai Committee of Science and Technology (19JC1411400), and the Laboratory Animal Science Foundation of Shanghai Committee of Science and Technology (19140902000, 201409005000).

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Author notes

  1. Baoling Zhu, Xiaowei Zhu, And Xiangfei Wang have contributed equally to this work.

Authors and Affiliations

  1. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

    Baoling Zhu, Xiaowei Zhu, Xiangfei Wang, Jian Wu, Suling Ding, Weiwei Zhang, Yunzeng Zou, Junbo Ge & Xiangdong Yang

  2. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China

    Baoling Zhu, Xiaowei Zhu, Xiangfei Wang, Jian Wu, Yunzeng Zou, Junbo Ge & Xiangdong Yang

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Contributions

XY and JW played leading roles in the study design and manuscript draft. BZ, XZ, and XW performed the experiments and wrote the manuscript. SD and WZ analyzed the data and helped the experimental implementation. YZ and JG contributed to the design of the study and the revision of the manuscript. All authors reviewed, discussed, and approved the final manuscript.

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Correspondence to Jian Wu or Xiangdong Yang.

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This article does not contain any studies with human participants performed by any of the authors. All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees.

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Associate Editor Junjie Xiao oversaw the review of this article

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Zhu, B., Zhu, X., Wang, X. et al. Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction. J. of Cardiovasc. Trans. Res. 15, 621–634 (2022). https://doi.org/10.1007/s12265-021-10172-2

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