Vascular endothelial S1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction
Vascular endothelial S1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction
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血管内皮 S1pr1 通过刺激心肌梗死后巨噬细胞修复性增殖来改善不良心脏重塑
DOI：
10.1093/cvr/cvaa046
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发表时间：
2021-02-01
影响因子：
10.8
通讯作者：
Zhang, Lin
中科院分区：
文献类型：
--
作者：
Kuang, Yashu;Li, Xiaolin;Zhang, Lin
目的内皮细胞（EC）稳态在正常生理心脏功能中起重要作用，其功能障碍显著影响心肌梗死（MI）后的病理性心脏重构。1-磷酸鞘氨醇受体1（S1 pr 1）在内皮细胞中高表达，在维持内皮功能中起重要作用。因此，我们假设，内皮S1 pr 1可能参与后MI cardiac remodeling.Methods和results我们的研究表明，内皮S1 pr 1的特定损失加剧后MI心脏重构和恶化的心功能不全。我们发现，内皮S1 pr 1的缺失显著减少了Ly 6c（低）巨噬细胞的积累，这对于MI后炎症的消退和心脏愈合至关重要。MI后心肌中修复性巨噬细胞的减少有助于内皮S1 pr 1缺陷对MI后心脏重构的不利影响。进一步的研究表明，内皮S1 pr 1的损失减少了Ly 6c（低）巨噬细胞的增殖，而S1 pr 1的药理学激活增强Ly 6c（低）巨噬细胞的增殖，从而改善心肌梗死后的心脏重塑。一项机制研究表明，S1 P/S1 pr 1激活ERK信号通路并增强集落刺激因子1（CSF 1）的表达，从而以细胞接触的方式促进Ly 6c（低）巨噬细胞增殖。结论心脏微血管内皮细胞通过S1 P/S1 PR 1/ERK/CSF 1信号通路促进损伤心脏修复性巨噬细胞增殖，从而改善MI后心脏重构。[图形]。
Aims Endothelial cell (EC) homoeostasis plays an important role in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodelling after myocardial infarction (MI). It has been shown that the sphingosine 1-phosphate receptor 1 (S1pr1) was highly expressed in ECs and played an important role in maintaining endothelial functions. We thus hypothesized that the endothelial S1pr1 might be involved in post-MI cardiac remodelling.Methods and results Our study showed that the specific loss of endothelial S1pr1 exacerbated post-MI cardiac remodelling and worsened cardiac dysfunction. We found that the loss of endothelial S1pr1 significantly reduced Ly6c(low) macrophage accumulation, which is critical for the resolution of inflammation and cardiac healing following MI. The reduced reparative macrophages in post-MI myocardium contributed to the detrimental effects of endothelial S1pr1 deficiency on post-MI cardiac remodelling. Further investigations showed that the loss of endothelial S1pr1-reduced Ly6c(low) macrophage proliferation, while the pharmacological activation of S1pr1-enhanced Ly6c(low) macrophage proliferation, thereby ameliorated cardiac remodelling after MI. A mechanism study showed that S1P/S1pr1 activated the ERK signalling pathway and enhanced colony-stimulating factor 1 (CSF1) expression, which promoted Ly6c(low) macrophage proliferation in a cell-contact manner. The blockade of CSF1 signalling reversed the enhancing effect of S1pr1 activation on Ly6c(low) macrophage proliferation and worsened post-MI cardiac remodelling.Conclusion This study reveals that cardiac microvascular endothelium promotes reparative macrophage proliferation in injured hearts via the S1P/S1PR1/ERK/CSF1 pathway and thus ameliorates post-MI adverse cardiac remodelling.[GRAPHICS].