Polysulfides介导Caveolin-1硫巯基化修饰在LDL跨内皮细胞穿胞及早期AS中的作用

项目名称： Polysulfides介导Caveolin-1硫巯基化修饰在LDL跨内皮细胞穿胞及早期AS中的作用

项目编号： No.81503072

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 卞芳

作者单位： 湖北文理学院

项目金额： 17.9万元

中文摘要： H2S具有抗AS作用，且其介导的硫巯基化修饰在心血管疾病中十分重要，但靶分子不明。近来报道，H2S通过其氧化产物Polysulfides发挥效应。“滞留-反应”学说认为，含ApoB脂蛋白(尤其LDL)在血管内皮下滞留是AS的始发环节。前期研究表明，LDL主要经小窝穿胞进入血管内皮下。预实验显示，H2S、Polysulfides可抑制LDL跨内皮细胞穿胞，且后者作用更明显。由此我们假设，H2S通过生成Polysulfides介导Caveolin-1(小窝标志蛋白)硫巯基化，抑制LDL穿胞进入血管内皮下，抑制AS发生。本项目拟以硫巯基化与穿胞的关系为出发点，通过建立LDL体外穿胞模型、培养人脐静脉、建立AS模型，在细胞、组织和动物水平探讨H2S-Polysulfides介导Caveolin-1硫巯基化在LDL跨内皮细胞穿胞及早期AS中的作用及机制，为H2S抗AS相关心血管疾病的研究提供新思路。

中文关键词： 动脉粥样硬化；低密度脂蛋白；穿胞；polysulfides；硫巯基化修饰

英文摘要： H2S has an anti-atherosclerotic effect, and H2S-induced S-sulfhydration of specific cysteine residues in target proteins has been implicated in cardiovascular diseases. However, a relatively small number of direct molecular targets of H2S have been identified. Recently, some study indicated that the oxidized products of H2S—Polysulfides are actually H2S-derived signaling molecules. The retention of apoB100-containing lipoproteins (e.g. Low density lipoprotein, LDL) in subendothelial space is the initiating process in AS, and is usually termed “response to retention” hypothesis. Our previous study found that caveolae mediated transcytosis is the major pathway for the LDL particles to traffic across endothelial cells (ECs). The preliminary experiments suggested that H2S and Polysulfides decreased the transcytosis of LDL across ECs, especially Polysulfides. Thus, we hypothesis that the protective role on AS is associated with H2S-Polysulfides-induced S-sulfhydration of caveolin-1(the marker of caveolae), which inhibits the transcytosis of LDL across ECs. This study aims to establish in-vitro transcytosis model to evaluate the effects of H2S-Polysulfides-induced S-sulfhydration on the transcytosis of LDL across ECs, and investigate the influence of S-sulfhydration on the subendothelial retention of LDL in human umbilical venous walls, and further analyze the effects of caveolin-1 S-sulfhydration on the formation of atherosclerotic lesions by establish AS animal model. Exploring the relation of H2S-Polysulfides-induced S-sulfhydration to the transcytosis of LDL, we will reveal a novel underlying mechanism of the protective role of H2S on cardiovascular diseases related to AS.

英文关键词： atherosclerosis;low density lipoprotein;transcytosis;polysulfides;s-sulfhydration