ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells.
ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells.
复制标题
ORMDL3 增加中国汉族人群动脉粥样硬化的风险，并介导氧化低密度脂蛋白诱导的内皮细胞自噬。
DOI：
10.1038/srep17194
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发表时间：
2015-11-25
影响因子：
4.6
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Ma X;Qiu R;Dang J;Li J;Hu Q;Shan S;Xin Q;Pan W;Bian X;Yuan Q;Long F;Liu N;Li Y;Gao F;Zou C;Gong Y;Liu Q
ORMDL 鞘脂生物合成调节因子 3 (ORMDL3) 是一种普遍证实的哮喘易感基因，最近已成为脂质代谢、炎症和内质网 (ER) 应激的重要调节剂，这些机制也与动脉粥样硬化 (AS) 密切相关。在这里，我们首先提出了调节 ORMDL3 表达的两个单核苷酸多态性（rs7216389 和 rs9303277）与 AS 风险显着相关的证据，以及中国汉族人群中 AS 病例与对照相比 ORMDL3 表达增加的证据。在检测其与 AS 的统计相关性后，我们进一步探讨了 ORMDL3 的功能相关性，并假设自噬在介导自噬中的潜在作用，因为自噬在脂质修饰、炎症和内质网应激时被激活。我们的结果表明，在内皮细胞中，氧化低密度脂蛋白（ox-LDL）上调 ORMDL3 表达，敲低 ORMDL3 不仅可以减轻 ox-LDL 诱导的作用，还可以减轻基础自噬。 BECN1 对于自噬启动和 ORMDL3 沉默至关重要，ORMDL3 抑制了 ox-LDL 诱导的以及基础 BECN1 表达。此外，ORMDL3 的缺失导致对 ox-LDL 诱导的细胞死亡更加敏感。综上所述，ORMDL3 可能是 AS 发病机制中介导内皮细胞自噬的致病基因。
ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) is a universally confirmed susceptibility gene for asthma and has recently emerged as a crucial modulator in lipid metabolism, inflammation and endoplasmic reticulum (ER) stress-the mechanisms also closely involved in atherosclerosis (AS). Here we first presented the evidence of two single nucleotide polymorphisms regulating ORMDL3 expression (rs7216389 and rs9303277) significantly associated with AS risk and the evidence of increased ORMDL3 expression in AS cases compared to controls, in Chinese Han population. Following the detection of its statistical correlation with AS, we further explored the functional relevance of ORMDL3 and hypothesized a potential role mediating autophagy as autophagy is activated upon modified lipid, inflammation and ER stress. Our results demonstrated that in endothelial cells oxidized low-density lipoprotein (ox-LDL) up-regulated ORMDL3 expression and knockdown of ORMDL3 alleviated not only ox-LDL-induced but also basal autophagy. BECN1 is essential for autophagy initiation and silencing of ORMDL3 suppressed ox-LDL-induced as well as basal BECN1 expression. In addition, deletion of ORMDL3 resulted in greater sensitivity to ox-LDL-induced cell death. Taken together, ORMDL3 might represent a causal gene mediating autophagy in endothelial cells in the pathogenesis of AS.