雌激素促进血管内皮硫化氢释放的非基因效应机制及其功能研究

项目名称： 雌激素促进血管内皮硫化氢释放的非基因效应机制及其功能研究

项目编号： No.81471426

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： 付晓东

作者单位： 广州医科大学

项目金额： 70万元

中文摘要： 雌激素可逆转绝经后女性血管内皮功能失调，降低动脉粥样硬化（AS）发生率，但其机制尚未阐明。在国家自然青年项目资助下，我们首次报道：17β-雌二醇（E2）可激活蛋白激酶G（PKG），快速促进血管内皮细胞释放气体信号分子硫化氢（H2S），改善内皮功能。E2通过何种非基因机制激活PKG？此非基因效应能否产生长期的抗AS作用？上述问题均需进一步研究。预实验结果表明，E2可增加PKG上游cGMP的水平，该作用被Gi蛋白抑制剂所阻断。由此，本项目拟：1、探讨膜雌激素受体α（mERα）调控鸟苷酸环化酶A进而激活cGMP/PKG/H2S的效应。2、研究Giα蛋白在其中的关键作用。3、在动物模型中激活或阻断此非基因效应，明确其抗AS作用。本项目在原创性工作的基础之上，深入揭示雌激素调控H2S这一非基因效应的内皮机制，证实其长期功能，并将提示，对非基因效应进行选择性干预，可能成为激素替代疗法防治AS的新策略。

中文关键词： 雌激素；非基因效应；硫化氢；血管内皮细胞；动脉粥样硬化

英文摘要： Estrogen has been proven to reverse vascular endothelial dysfunction and reduce the incidence of atherosclerosis in postmenopausal women, while the detailed mechanisms remain obscure. We have discovered a novel mechanism for estrogen's endothelial actions, that is, 17β-estradiol (E2) activates protein kinase G (PKG) and rapidly promotes the release of hydrogen sulfide (H2S) from vascular endothelial cells, resulting in the improvement of endothelial function. However, what is the exact nongenomic mechanism responsible for the above mentioned action? Does this nongenomic pathway provide the long-term anti-atherogenic effect? Further efforts are needed to answer these questions. The preliminary results of this project showed that E2 elevated cGMP level, which was blocked by Gi signaling inhibitor pertussis toxin. Based on these results, the present project aims to explore the following issues. Firstly, we plan to investigate the modulatory effect of membrane estrogen receptor α (ERα) on particulate guanylyl cyclase A activity and the subsequent activation of cGMP/PKG/H2S. Secondly, the critical role of Giα protein in this process will be confirmed. Finally, we will use animal model to observe the alteration of estrogen's anti-atherogenesis effect when this nongenomic action is activated or blocked. The present project aims to explore the nongenomic mechanism and function of E2-stimulated H2S release and it will shed light on the novel strategy of estrogen replacement therapy by the selective interference of nongenomic effects.

英文关键词： Estrogen;Nongenomic Effect;Sulfide Hydrogen;Vascular Endothelial Cells;Atherosclerosis