Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Br J Pharmacol. 2021 Oct;178(20):4048-4068. doi: 10.1111/bph.15583. Epub 2021 Jul 6.
Neointimal hyperplasia (NIH) is the fundamental cause for vascular diseases and vascular smooth muscle cell (VSMC) dysregulation has been widely implicated in NIH. Neutrophil elastase is a potential therapeutic target for multiple diseases. We investigated the role of neutrophil elastase in VSMC functions and injury-induced NIH and explored the therapeutic potential of targeting neutrophil elastase in NIH.
VSMCs were used to analyse the effects of neutrophil elastase. Proteomic analysis was used to identify potential neutrophil elastase targets. Artery injury model and neutrophil elastase inhibitor GW311616A were used to investigate the role of neutrophil elastase in NIH.
TNF-α up-regulated neutrophil elastase in VSMCs through modulating GAPBα/Runx1/CEBPα/c-Myb signalling. Up-regulated neutrophil elastase promoted VSMC migration, proliferation and inflammation. Toll-like receptor 4 (TLR4) was identified as a target protein for neutrophil elastase in VSMCs and the TLR4/MyD88/IRAK1/TRAF6/NF-κB regulatory axis was shown to be the signalling pathway for neutrophil elastase in VSMC pathology. Importantly, TLR4 inhibition abolished neutrophil elastase-mediated VSMC dysregulation. Injury-induced NIH was significantly reduced in both neutrophil elastase-deficient mice and mice treated with GW311616A. The formation of neutrophil extracellular traps was impaired in injured arteries from neutrophil elastase-deficient mice. Finally, a similar role for neutrophil elastase in human VSMC pathology was confirmed and we observed higher expression levels of neutrophil elastase but lower expression levels of TLR4 in human atherosclerotic lesions.
We provide new insight into the molecular mechanisms underlying NIH and identify neutrophil elastase as a potential therapeutic target for vascular disease.
血管疾病的根本原因是新生内膜增生（NIH），血管平滑肌细胞（VSMC）失调已被广泛认为与 NIH 有关。中性粒细胞弹性蛋白酶是多种疾病的潜在治疗靶点。我们研究了中性粒细胞弹性蛋白酶在 VSMC 功能和损伤诱导的 NIH 中的作用，并探讨了靶向 NIH 中中性粒细胞弹性蛋白酶的治疗潜力。
使用 VSMC 分析中性粒细胞弹性蛋白酶的作用。蛋白质组学分析用于鉴定潜在的中性粒细胞弹性蛋白酶靶标。使用动脉损伤模型和中性粒细胞弹性蛋白酶抑制剂 GW311616A 研究中性粒细胞弹性蛋白酶在 NIH 中的作用。
TNF-α 通过调节 GAPBα/Runx1/CEBPα/c-Myb 信号通路上调 VSMCs 中的中性粒细胞弹性蛋白酶。上调的中性粒细胞弹性蛋白酶促进 VSMC 迁移、增殖和炎症。Toll 样受体 4（TLR4）被鉴定为 VSMCs 中中性粒细胞弹性蛋白酶的靶蛋白，TLR4/MyD88/IRAK1/TRAF6/NF-κB 调节轴被证明是 VSMC 病理中性粒细胞弹性蛋白酶的信号通路。重要的是，TLR4 抑制消除了中性粒细胞弹性蛋白酶介导的 VSMC 失调。中性粒细胞弹性蛋白酶缺陷小鼠和 GW311616A 治疗小鼠的损伤诱导 NIH 明显减少。中性粒细胞弹性蛋白酶缺陷小鼠损伤动脉中中性粒细胞细胞外陷阱的形成受损。最后，还证实了中性粒细胞弹性蛋白酶在人 VSMC 病理中的类似作用，并且我们观察到人动脉粥样硬化病变中中性粒细胞弹性蛋白酶的表达水平较高，而 TLR4 的表达水平较低。
我们提供了 NIH 分子机制的新见解，并将中性粒细胞弹性蛋白酶鉴定为血管疾病的潜在治疗靶点。
