HuR在尼古丁促进内皮功能损伤及动脉粥样硬化斑块形成和破裂中的作用及机制研究

内皮功能障碍是动脉粥样硬化（AS）的起始和关键环节，而烟草的主要成分尼古丁(nicotine)能够促进AS斑块的形成,但具体的作用机制不明。我们的前期工作首次发现，尼古丁处理内皮细胞能够造成一氧化氮合成反应中的重要酶鸟苷三磷酸环水解酶1(GTPCH1)的降低。此外尼古丁能够抑制RNA结合蛋白人类抗原R (HuR)的出核，并且HuR可以和GTPCH1 mRNA结合。据此我们设想，尼古丁通过抑制HuR与GTPCH1 mRNA结合从而造成内皮功能的损伤。本课题拟运用多种实验手段，体外与体内研究相结合，鉴定GTPCH1是HuR的靶基因；探讨HuR在尼古丁促进内皮功能损伤中的作用；明确尼古丁促进AS斑块形成和破裂的机制。通过研究HuR是否调节GTPCH1的mRNA稳定性，旨在阐明尼古丁促进AS的分子机制。此研究将拓展我们对尼古丁和GTPCH1生物学功能的认识，为寻找抗AS的药物提供新靶点和思路。

Endothelial dysfunction is the initial and crucial step for atherosclerotic formation, which is also induced by nicotine, a major component of cigarette smoke. However, the molecular mechanism by which nicotine induces atherosclerosis remained poorly understood. Our preliminary studies showed that nicotine could reduce the levels of guanosine 5’-triphosphate cyclohydrolase 1 (GTPCH1), an important enzyme in NO formation in the endothelial cells. We further found that nicotine inhibited translocation of RNA-binding protein, human antigen R (HuR) from nucleus into cytosol. Besides, HuR may bind with GTPCH1 mRNA. The central hypothesis of the current study is that nicotine causes endothelial dysfunction by inhibiting the binding of HuR and GTPCH1 mRNA. Comprehensive experimental approaches will be used (1) to identify whether GTPCH1 is the target of HuR; (2) to explore the role of HuR in nicotine-induced endothelial dysfunction; and (3) to define the mechanism by which nicotine induces atherosclerotic formation/rupture. This powerful combination of in vitro and in vivo techniques and gain/loss-of-function approaches will yield important insights into how nicotine induces atherosclerosis. Our work will increase our understanding about the roles of nicotine and GTPCH1, and also provide scientific evidence for looking for anti-atherosclerotic drugs.