LncRNA NEXN-AS1/NEXN途径介导OX-LDL对细胞焦亡和AS的影响及机制研究

Pyroptosis is a newly found form of programmed cell death, which is dependent on caspase-1 activation and leads to the release of pro-inflammatory cytokines. Oxidized low-density lipoprotein (OX-LDL) promotes caspase-1 mediated pyroptotic cell death and plays a crucial role in the initiation and progression of atherosclerosis. In addition, long non-coding RNA (lncRNA) is involved in OX-LDL-induced atherosclerosis development. Our preliminary data showed that expression levels of lncRNA NEXN-AS1 and NEXN were significantly down-regulated by treatment with OX-LDL in THP-1 macrophages. Furthermore, OX-LDL-induced pyroptosis could be markedly inhibited by overexpression of NEXN in THP-1 macrophages. We also demonstrated NEXN expression levels were markedly up-regulated while pyroptosis was markedly decreased by overexpression of NEXN-AS1 in THP-1 macrophages. Thus, we hypothesize that pyroptosis and atherosclerosis development can be affected by OX-LDL through inhibiting lncRNA NEXN-AS1 and NEXN expression. In this study, we aim to explore the effect and mechanism of OX-LDL/ lncRNA NEXN-AS1/ NEXN pathway on pyroptosis and atherosclerosis development by enhancing or inhibiting expression of lncRNA NEXN-AS1 and/or NEXN. Therefore, our study may provide a new scientific evidence to establish OX-LDL/ lncRNA NEXN-AS1/NEXN pathway as a new target for regulation of pyroptosis and prevention of atherosclerosis.

细胞焦亡是近年来被发现的一种新型程序性细胞死亡方式，其特征为依赖半胱天冬酶-1(caspase-1)并伴有大量促炎症因子释放。研究表明OX-LDL可通过调节细胞焦亡进而影响AS发生发展。LncRNA在OX-LDL促进的AS中发挥重要的作用。我们的前期预实验结果证明OX-LDL可下调巨噬细胞中LncRNA NEXN-AS1和NEXN表达，NEXN可抑制OX-LDL诱导的细胞焦亡，过表达NEXN-AS1能明显促进NEXN表达并抑制巨噬细胞焦亡。因此我们提出LncRNA NEXN-AS1/NEXN途径可能介导OX-LDL调控细胞焦亡从而影响AS发生发展。本项目拟通过增强/抑制NEXN-AS1和/或NEXN表达，观察OX-LDL/ LncRNA NEXN-AS1/NEXN途径对细胞焦亡和AS的影响并探讨相关机制，为确定该途径可作为调控细胞焦亡和防治AS的新靶点提供科学依据。

细胞焦亡是近年来被发现的一种新型程序性细胞死亡方式，其特征为依赖半胱天冬酶-1(caspase-1)并伴有大量促炎症因子释放。研究表明OX-LDL可通过调节细胞焦亡进而影响AS发生发展。我们的结果证明OX-LDL可下调巨噬细胞中LncRNA NEXN-AS1和NEXN表达，NEXN可抑制OX-LDL诱导的细胞焦亡，过表达NEXN-AS1能明显促进NEXN表达并抑制巨噬细胞焦亡。同时在内皮细胞中过表达NEXN-AS1，可上调NEXN的表达，来抑制TLR4-NFκB通路和炎症基因的表达，从而抑制单核细胞对内皮细胞的黏附作用。因此LncRNA NEXN-AS1/NEXN途径介导了细胞焦亡，更重要的是NEXN-AS1/NEXN途径抑制TLR4-NFκB通路和炎症，从而抑制AS发生发展，本项目探究NEXN-AS1和NEXN对细AS影响机制，为防治AS提供了新靶点和科学依据。