Roles of Nicotine in the Development of Intracranial Aneurysm Rupture.
Roles of Nicotine in the Development of Intracranial Aneurysm Rupture.
复制标题
DOI：
10.1161/strokeaha.118.021706
复制
发表时间：
2018-10
期刊：
影响因子：
8.3
通讯作者：
Hashimoto T
中科院分区：
文献类型：
--
作者：
Kamio Y;Miyamoto T;Kimura T;Mitsui K;Furukawa H;Zhang D;Yokosuka K;Korai M;Kudo D;Lukas RJ;Lawton MT;Hashimoto T
吸烟被认为是颅内动脉瘤破裂的一个强烈危险因素。尼古丁是烟草产品的主要生物活性成分。尼古丁与含有 α7 亚基 (α7*-nAChR) 的血管细胞烟碱乙酰胆碱受体的相互作用被认为可促进局部炎症和持续的血管生成。在这项研究中，我们使用小鼠颅内动脉瘤模型，评估了尼古丁暴露和 α7*-nAChR 激活对动脉瘤破裂发展的潜在贡献。颅内动脉瘤是由脱氧皮质酮盐诱导的高血压和单次弹性蛋白酶注射到小鼠脑脊液中联合诱导的。接触尼古丁或α7*-nAChR选择性激动剂显着增加动脉瘤破裂率。同时接触 α7*-nAChR 拮抗剂消除了尼古丁的有害作用。此外，在平滑肌细胞特异性 α7*-nAChR 亚基敲除小鼠中，尼古丁不存在促进动脉瘤破裂的作用，但在内皮细胞或巨噬细胞上缺乏 α7*-nAChR 的小鼠中则不然。尼古丁治疗增加了血管内皮生长因子、血小板衍生生长因子-B 和炎症细胞因子的 mRNA 水平。 α7*-nAChR 拮抗剂可逆转尼古丁诱导的这些生长因子和细胞因子的上调。我们的研究结果表明，尼古丁暴露通过对血管平滑肌细胞 α7*-nAChR 的作用促进动脉瘤破裂。
Tobacco cigarette smoking is considered to be a strong risk factor for intracranial aneurysmal rupture. Nicotine is a major biologically-active constituent of tobacco products. Nicotine’s interactions with vascular cell nicotinic acetylcholine receptors containing α7 subunits (α7*-nAChR) are thought to promote local inflammation and sustained angiogenesis. In this study, using a mouse intracranial aneurysm model, we assessed potential contributions of nicotine exposure and activation of α7*-nAChR to the development of aneurysmal rupture. Intracranial aneurysms were induced by a combination of deoxycorticosterone-salt induced hypertension and a single elastase injection into cerebrospinal fluid in mice. Exposure to nicotine or an α7*-nAChR-selective agonist significantly increased aneurysm rupture rate. Co-exposure to an α7*-nAChR antagonist abolished nicotine’s deleterious effect. Additionally, nicotine’s promotion of aneurysm rupture was absent in smooth muscle cell-specific α7*-nAChR subunit knockout mice, but not in mice lacking α7*-nAChR on endothelial cells or macrophages. Nicotine treatment increased the mRNA levels of vascular endothelial growth factor, platelet-derived growth factor-B, and inflammatory cytokines. α7*-nAChR antagonist reversed nicotine-induced up-regulation of these growth factors and cytokines. Our findings indicate that nicotine exposure promotes aneurysmal rupture through actions on vascular smooth muscle cell α7*-nAChR.