nAChRα1受体在尼古丁诱导的动脉粥样硬化中的作用及分子机制

Nicotine is an important substance in tobacco in promoting atherosclerosis. The molecular mechanism of nicotine in atherogenesis is not clear and is the research focus. The current studies mainly focused on the effect of the alpha 7 nicotinic receptor in atherosclerosis and inflammation. However, the study results are full of contradictions. Alpha 1 nicotinic receptor (nAChRα1) is one of the important receptor to nicotine, which is widely distributed in vascular smooth muscle cells, macrophages and endothelial cells. The role of nAChRα1 in nicotine-mediated atherosclerosis has not been reported both home and abroad. One study shows that nicotine increases nAChRα1 expression in the tracheal endothelial cells, and the increment of nAChRα1 will activate Calpain-1, which modulates the MMP2 activity of vascular smooth muscle cells. Both Calpain-1 and MMP2 are important proteases in promotion of atherosclerosis. Our previous study showed that nicotine can increase MMP2 expression in both smooth muscle cells and macrophages. We also found that nicotine increases the expression of MMP-2 and CD68 positive cells in the aortic tissue. Based on the above evidences, we suppose that nicotine can promote atherosclerosis through the nAChRα1-Calpain-1-MMP2 axis. In this study, we use ApoE-/- mice to establish atherosclerotic model, and use gene silencing (nAChRα1 siRNA) technology to test the effect nAChRα1- Calpain-1-MMP2 axis on atherosclerosis induced by nicotine; additionally, we want to demonstrate that nicotine is involved in the process of VSMC migration/proliferation and macrophage inflammation via nAChRα1. This study is expected to provide scientific theoretical basis for research on nicotine-induced atherosclerosis.

尼古丁是烟草中促进动脉粥样硬化（AS）的重要物质，其促AS的分子机制不清楚且是目前研究的热点。nAChRα1受体是尼古丁的重要受体，其在尼古丁促AS中的作用国内外未见报道。研究显示，尼古丁使气管内皮细胞nAChRα1表达增加, nAChRα1可以使Calpain-1激活，而Calpain-1调控平滑肌细胞MMP2活性。Calpain-1和MMP2是促进AS发展的重要的蛋白酶。我们前期研究发现尼古丁可以使平滑肌细胞和巨噬细胞的MMP2表达增加。由此假设：尼古丁通过nAChRα1受体，激活Calpain-1-MMP2轴促进AS的形成。本研究利用ApoE-/-小鼠建立AS模型，采用基因沉默等技术首先探讨nAChRα1-Calpain-1-MMP2轴调控尼古丁诱导的AS；同时，探讨尼古丁通过 nAChRα1参与VSMC迁移/增殖和促巨噬细胞炎症的机制，为尼古丁致AS的研究提供科学理论基础。

尼古丁是烟草中促进动脉粥样硬化(AS)的重要物质，其促AS的分子机制不清楚且是目前研究的热点。nAChRα1受体是尼古丁的重要受体，其在尼古丁促AS中的作用国内外未见报道。本课题在第一部分完成验证“尼古丁通过nAChRα1受体,激活Calpain-1-MMP2轴促进AS的形成”假设的基础上，在第二、三、四部分分别通过对“尼古丁通过nAChRα1致动脉粥样硬化的核转录机制的探讨”、“尼古丁通过调节自噬-溶酶体机制介导组织蛋白酶S（CTSS）的合成和分泌，促进AS的进展”及“尼古丁促进巨噬细胞焦亡从而促进AS进展”的研究中探讨了尼古丁通过nAChRα1参与VSMC迁移/增殖和促巨噬细胞炎症的机制，为尼古丁致AS的研究提供科学理论基础。本项目研究成果发表SCI论文4 篇，核心期刊2 篇。培养已毕业科研型硕士2 名、在读科研型博士1 名及科研型硕士1 名。