Neutrophil elastase promotes neointimal hyperplasia by targeting toll‐like receptor 4 (TLR4)–NF‐κB signalling

Abstract

Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusion and Implications We provide new insight into the molecular mechanisms underlying NIH and identify neutrophil elastase as a potential therapeutic target for vascular disease.

IMP3 promotes re‐endothelialization after arterial injury via increasing stability of VEGF mRNAhv

“…According to our available results, endothelial cells express IMP3 at a relatively low level in the uninjured condition; upon receiving wire‐injured surgery, expression level of IMP3 in endothelial cells followed a trend of early elevation and late decrease. This is highly consistent with the pathological changes of the disease 37,47 . During the early stage of injury, in response to the loss of large number of endothelial cells, the remaining endothelial cells begin to enter a state of proliferation, by up‐regulating the expression of IMP3.…”

“…This is highly consistent with the pathological changes of the disease. 37 , 47 During the early stage of injury, in response to the loss of large number of endothelial cells, the remaining endothelial cells begin to enter a state of proliferation, by up‐regulating the expression of IMP3. Such effect reaches its peak at Day 14; when the endothelial repair process has been largely completed, the demand for cell proliferation is also reduced progressively.…”

Pathogenesis and Clinical Significance of In-Stent Restenosis in Patients with Diabetes

“…Paclitaxel has been shown to dysregulate the toll-like receptor 4 (TLR4) and the NOD-, LRR-, and pyrin domaincontaining protein 3 (NLRP3) inflammasome [118]. In a noteworthy study, TLR4 was shown to be a target for neutrophil elastase by which this enzyme takes a part in neointimal formation [119].…”

Specialized Proresolving Lipid Mediators: A Potential Therapeutic Target for Atherosclerosis

“…On another note, Yang et al [ 91 ] performed a study with murine and human aortic tissues. They evidenced a novel mechanism in promoting VSMC migration, proliferation, and inflammation in the setting of intimal hyperplasia, via neutrophil elastase (NE).…”