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首页> 外文期刊>Redox Biology >Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress
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Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress

机译：胆碱能抗炎途径通过抑制炎症和氧化应激来抑制新内膜增生

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Neointimal hyperplasia as a consequence of vascular injury is aggravated by inflammatory reaction and oxidative stress. The α7 nicotinic acetylcholine receptor (α7nAChR) is a orchestrator of cholinergic anti-inflammatory pathway (CAP), which refers to a physiological neuro-immune mechanism that restricts inflammation. Here, we investigated the potential role of CAP in neointimal hyperplasia using α7nAChR knockout (KO) mice. Male α7nAChR-KO mice and their wild-type control mice (WT) were subjected to wire injury in left common carotid artery. At 4 weeks post injury, the injured aortae were isolated for examination. The neointimal hyperplasia after wire injury was significantly aggravated in α7nAChR-KO mice compared with WT mice. The α7nAChR-KO mice had increased collagen contents and vascular smooth muscle cells (VSMCs) amount. Moreover, the inflammation was significantly enhanced in the neointima of α7nAChR-KO mice relative to WT mice, evidenced by the increased expression of tumor necrosis factor-α/interleukin-1β, and macrophage infiltration. Meanwhile, the chemokines chemokine (C-C motif) ligand 2 and chemokine (CXC motif) ligand 2 expression was also augmented in the neointima of α7nAChR-KO mice compared with WT mice. Additionally, the depletion of superoxide dismutase (SOD) and reduced glutathione (GSH), and the upregulation of 3-nitrotyrosine, malondialdehyde and myeloperoxidase were more pronounced in neointima of α7nAChR-KO mice compared with WT mice. Accordingly, the protein expression of NADPH oxidase 1 (Nox1), Nox2 and Nox4, was also higher in neointima of α7nAChR-KO mice compared with WT mice. Finally, pharmacologically activation of CAP with a selective α7nAChR agonist PNU-282987, significantly reduced neointima formation, arterial inflammation and oxidative stress after vascular injury in C57BL/6 mice. In conclusion, our results demonstrate that α7nAChR-mediated CAP is a neuro-physiological mechanism that inhibits neointima formation after vascular injury via suppressing arterial inflammation and oxidative stress. Further, these results imply that targeting α7nAChR may be a promising interventional strategy for in-stent stenosis.
机译：炎性反应和氧化应激加剧了由于血管损伤而引起的新内膜增生。 α7烟碱乙酰胆碱受体（α7nAChR）是胆碱能抗炎途径（CAP）的协调者，它是限制炎症的生理神经免疫机制。在这里，我们研究了使用α7nAChR基因敲除（KO）小鼠在新内膜增生中CAP的潜在作用。雄性α7nAChR-KO小鼠及其野生型对照小鼠（WT）左颈总动脉受到钢丝损伤。受伤后4周，分离受伤的主动脉进行检查。与野生型小鼠相比，α7nAChR-KO小鼠的钢丝损伤后新内膜增生明显加重。 α7nAChR-KO小鼠的胶原蛋白含量和血管平滑肌细胞（VSMC）数量增加。此外，相对于野生型小鼠，α7nAChR-KO小鼠新内膜的炎症显着增强，这由肿瘤坏死因子-α/白介素-1β的表达增加和巨噬细胞浸润所证明。同时，与WT小鼠相比，α7nAChR-KO小鼠的新内膜中趋化因子趋化因子（C-C基序）配体2和趋化因子（CXC基序）配体2的表达也增加。此外，与WT小鼠相比，α7nAChR-KO小鼠新内膜中超氧化物歧化酶（SOD）的减少和谷胱甘肽（GSH）的减少以及3-硝基酪氨酸，丙二醛和髓过氧化物酶的上调更为明显。因此，与WT小鼠相比，α7nAChR-KO小鼠的新内膜中NADPH氧化酶1（Nox1），Nox2和Nox4的蛋白表达也更高。最后，在C57BL / 6小鼠中，用选择性α7nAChR激动剂PNU-282987对CAP进行药理激活，可显着减少血管损伤后新内膜的形成，动脉炎症和氧化应激。总之，我们的结果表明，α7nAChR介导的CAP是一种神经生理机制，可通过抑制动脉炎症和氧化应激来抑制血管损伤后新内膜的形成。此外，这些结果暗示靶向α7nAChR可能是支架内狭窄的有希望的介入策略。

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