Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction,Journal of Cardiovascular Translational Research

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Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction
Journal of Cardiovascular Translational Research ( IF 2.4 ) Pub Date : 2021-11-03 , DOI: 10.1007/s12265-021-10172-2
Baoling Zhu _{1,

2} , Xiaowei Zhu _{1,

2} , Xiangfei Wang _{1,

2} , Jian Wu _{1,

2} , Suling Ding ₁ , Weiwei Zhang ₁ , Yunzeng Zou _{1,

2} , Junbo Ge _{1,

2} , Xiangdong Yang _{1,

2}

Affiliation

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.

中文翻译：

组胺缺乏促进心肌梗死后受损心脏中表达 HDC 的 CD11b+ 髓样细胞的肌成纤维细胞转化

心肌梗塞 (MI) 是导致心力衰竭发展的重要因素。组氨酸脱羧酶 (HDC) 是将l-组氨酸转化为组胺的独特酶，在 CD11b ⁺未成熟骨髓细胞中高度表达。然而，表达 HDC 的巨噬细胞与心脏肌成纤维细胞之间的关系仍有待解释。在这里，我们证明了 GFP（绿色荧光蛋白）标记的 HDC ⁺ CD11b ⁺骨髓前体及其后代可以在心肌间质中分化成成纤维细胞样细胞。此外，我们证明 CD11b ⁺ Ly6C ⁺单核细胞/巨噬细胞，而不是 CD11b ⁺ Ly6G ⁺粒细胞被确定为骨髓来源的肌成纤维细胞转化的主要细胞来源，可通过组胺 H1 和 H2 受体依赖性信号通路进行调节。使用 HDC 敲除小鼠，我们发现组胺缺乏部分通过上调 Krüppel 样因子 5 (KLF5) 的表达来促进 Ly6C ^{+巨噬细胞和心脏纤维化的肌成纤维细胞转化。}总之，我们的数据揭示了 HDC 在调节骨髓来源的巨噬细胞向肌成纤维细胞转化中的核心作用，同时还确定了一种与组胺受体 (HR)-KLF5 相关的信号通路，该通路介导 MI 后的心肌纤维化。