Kuang Yashu, Li Xiaolin, Liu Xiuxiang, Wei Lu, Chen Xiaoli, Liu Jie, Zhuang Tao, Pi Jingjiang, Wang Yanfang, Zhu Chenying, Gong Xin, Hu Hao, Yu Zuoren, Li Jiming, Yu Ping, Fan Huimin, Zhang Yuzhen, Liu Zhongmin, Zhang Lin
Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai 200120, China.
Medical School, Internal Medicine Department, Jinggangshan University, Ji'an 343009, China.
Cardiovasc Res. 2021 Jan 21;117(2):585-599. doi: 10.1093/cvr/cvaa046.
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.
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 Ly6clow 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 Ly6clow macrophage proliferation, while the pharmacological activation of S1pr1-enhanced Ly6clow 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 Ly6clow macrophage proliferation in a cell-contact manner. The blockade of CSF1 signalling reversed the enhancing effect of S1pr1 activation on Ly6clow macrophage proliferation and worsened post-MI cardiac remodelling.
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.
内皮细胞（EC）稳态在正常生理性心脏功能中起重要作用，其功能障碍会显著影响心肌梗死（MI）后的病理性心脏重塑。研究表明，鞘氨醇-1-磷酸受体1（S1pr1）在EC中高表达，并在维持内皮功能中起重要作用。因此，我们推测内皮S1pr1可能参与MI后的心脏重塑。
我们的研究表明，内皮S1pr1的特异性缺失加剧了MI后的心脏重塑并恶化了心脏功能障碍。我们发现，内皮S1pr1的缺失显著减少了Ly6clow巨噬细胞的积聚，这对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导致了内皮S1pr1缺乏对MI后心脏重塑的有害影响。进一步研究表明，内皮S1pr1的缺失降低了Ly6clow巨噬细胞的增殖，而S1pr1的药理学激活增强了Ly6clow巨噬细胞的增殖，从而改善了MI后的心脏重塑。机制研究表明，S1P/S1pr1激活ERK信号通路并增强集落刺激因子1（CSF1）的表达，以细胞接触方式促进Ly6clow巨噬细胞增殖。CSF1信号通路的阻断逆转了S1pr1激活对Ly6clow巨噬细胞增殖的增强作用，并恶化了MI后的心脏重塑。
本研究揭示，心脏微血管内皮通过S1P/S1PR1/ERK/CSF1途径促进受损心脏中修复性巨噬细胞的增殖，从而改善MI后的不良心脏重塑。
