Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis
Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis
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内皮向间质转化有助于尼古丁诱导的动脉粥样硬化
DOI：
10.7150/thno.42470
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhang, Yong
中科院分区：
文献类型：
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作者：
Qin, Wei;Zhang, Longyin;Zhang, Yong
原理：通过吸烟暴露于尼古丁与动脉粥样硬化密切相关。然而，对潜在的机制仍然知之甚少。目前的研究旨在确定内皮细胞间质转化（EndMT）是否有助于尼古丁诱导的动脉粥样硬化。方法：ApoE-/-小鼠在饮水中给予尼古丁12周。通过主动脉根部的免疫组化染色和主动脉内膜RNA分析来确定尼古丁对EndMT的影响。在人主动脉内皮细胞（HAECs）上建立尼古丁处理的体外细胞模型。采用实时荧光定量PCR、Western blot和免疫荧光染色检测尼古丁对EndMT相关标志物ERK 1/2和Snail表达的影响。结果：尼古丁治疗导致ApoE-/-小鼠的动脉粥样硬化斑块更大。尼古丁处理小鼠的血管内皮细胞显示间充质表型，表明EndMT。此外，尼古丁诱导的EndMT过程伴随着细胞骨架重组和屏障功能受损。α7烟碱乙酰胆碱受体（α 7 nAChR）在HAECs中高表达，其拮抗剂能有效减轻尼古丁诱导的EndMT和动脉粥样硬化病变。进一步的实验表明，ERK 1/2信号被尼古丁激活，导致Snail上调。用抑制剂阻断ERK 1/2或用小干扰RNA沉默Snail有效地保留了尼古丁刺激后的内皮表型。结论：我们的研究提供了证据，EndMT有助于尼古丁的促动脉粥样硬化特性。尼古丁通过α 7 nAChR-ERK 1/2-Snail信号通路诱导内皮细胞EndMT EndMT可能是吸烟相关内皮功能障碍和心血管疾病的治疗靶点。
Rationale: Nicotine exposure via cigarette smoking is strongly associated with atherosclerosis. However, the underlying mechanisms remain poorly understood. The current study aimed to identify whether endothelial to mesenchymal transition (EndMT) contributes to nicotine-induced atherosclerosis. Methods: ApoE-/- mice were administered nicotine in their drinking water for 12 weeks. The effects of nicotine on EndMT were determined by immunostaining on aortic root and RNA analysis in aortic intima. In vitro nicotine-treated cell model was established on human aortic endothelial cells (HAECs). The effects of nicotine on the expression of EndMT-related markers, ERK1/2 and Snail were quantified by real-time PCR, western blot and immunofluorescent staining. Results: Nicotine treatment resulted in larger atherosclerotic plaques in ApoE-/- mice. The vascular endothelial cells from nicotine-treated mice showed mesenchymal phenotype, indicating EndMT. Moreover, nicotine-induced EndMT process was accompanied by cytoskeleton reorganization and impaired barrier function. The α7 nicotine acetylcholine receptor (α7nAChR) was highly expressed in HAECs and its antagonist could effectively relieve nicotine-induced EndMT and atherosclerotic lesions in mice. Further experiments revealed that ERK1/2 signaling was activated by nicotine, which led to the upregulation of Snail. Blocking ERK1/2 with inhibitor or silencing Snail by small interfering RNA efficiently preserved endothelial phenotype upon nicotine stimulation. Conclusion: Our study provides evidence that EndMT contributes to the pro-atherosclerotic property of nicotine. Nicotine induces EndMT through α7nAChR-ERK1/2-Snail signaling in endothelial cells. EndMT may be a therapeutic target for smoking-related endothelial dysfunction and cardiovascular disease.