尼古丁对血管外周脂肪组织的影响在动脉粥样硬化中的作用及机制研究

项目名称： 尼古丁对血管外周脂肪组织的影响在动脉粥样硬化中的作用及机制研究

项目编号： No.81470471

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王毅

作者单位： 上海交通大学

项目金额： 68万元

中文摘要： 年轻冠心病患者吸烟和超重/肥胖同时暴露率显著升高，提示烟草和脂肪组织相互作用可能影响了动脉粥样硬化（AS）启动和进展，但该作用及机制尚待探讨。尼古丁通过nAChRs受体作用于内皮细胞、巨噬细胞和血管平滑肌细胞，影响NF-kB活性和表达，促进炎症趋化因子和表面受体表达及细胞趋化迁移。血管外周脂肪与AS相关，但脂肪细胞是否存在尼古丁nAChRs-NF-kB调控轴并影响AS过程未见报道。由此推测，尼古丁诱导血管外周脂肪组织，通过nAChRs-NF-kB轴调控其合成分泌等功能，影响AS形成。为验证该假设，体内体外观察尼古丁诱导血管外周脂肪组织nAChRs-NF-kB轴对AS影响和尼古丁诱导脂肪细胞对巨噬细胞和平滑肌细胞的炎症趋化因子、脂蛋白受体等表达，及对平滑肌细胞等趋化和表型的影响，并用临床样本验证。本项目将阐明尼古丁诱导血管外周脂肪组织影响AS的作用和机制，为临床药物和靶向治疗提供帮。

中文关键词： 尼古丁；血管外周脂肪组织；动脉粥样硬化；烟碱型乙酰胆碱受体；核因子-κB

英文摘要： Many manuscripts and preliminary studies found that the probability of coexistence of smoking and obesity significantly increases in young patients with coronary artery disease. It suggests that the interaction between tobacco and adipose tissue may affect the occurrence and development of atherosclerosis(AS). However the role and mechanism remains to be explored. Nicotine impacts the activity and expression of NF-?B, and promotes the expression of inflammatory chemokines, cell surface receptors and cell chemotaxis, migration and proliferation through its characteristic nAChRs nicotine receptors on endothelial cells, macrophages and vascular smooth muscle cells. Perivascular adipose tissue associated with AS, however, whether adipocyte nicotine nAChRs-NF-?B regulation axis exists and affects the atherosclerotic process has not been reported. The Hypothesis would be that nicotine induces peripheral vascular adipose tissue and regulates their synthesis, secretion and other functions through nAChRs-NF-?B axis, then impacts atherosclerotic formation. To evaluate the hypothesis, this study uses gene knockout and RNAi technologies to observe the impact of nicotine-induced adipocyte nAChRs-NF-?B axis on AS, the expression of adipocyte on inflammatory chemokines, lipoprotein receptors and proteases of endothelial cells, macrophages and vascular smooth musclecells induced by nicotine, and the impact on macrophages and smooth muscle cell chemotaxis and phenotype in vitro and vivo. Besides, the hypothesis is verified by clinical samples. The project will clarify the effects of nicotine-induced perivascular adipose tissue on the functions and mechanism of AS, providing help for clinical medicine and targeted therapy.

英文关键词： nicotine;perivascular adipose tissue;atherosclerosis;nicotinic acetylcholine receptors;nuclear factor-kappa B