Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a.
Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a.
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DOI：
10.1161/circulationaha.114.013675
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发表时间：
2015-03-03
期刊：
影响因子：
37.8
通讯作者：
Shyy JY
中科院分区：
文献类型：
--
作者：
Chen Z;Wen L;Martin M;Hsu CY;Fang L;Lin FM;Lin TY;Geary MJ;Geary GG;Zhao Y;Johnson DA;Chen JW;Lin SJ;Chien S;Huang HD;Miller YI;Huang PH;Shyy JY
氧化应激激活内皮天然免疫功能，破坏内皮功能，包括eNOS来源的NO生物利用度。在这里，我们假设氧化应激诱导固醇调节元件结合蛋白2(SREBP2)和microRNA-92a(miR-92a)，进而激活内皮天然免疫反应，导致内皮功能障碍。使用受到不同氧化应激挑战的培养内皮细胞(ECs)、高胆固醇斑马鱼和Ang II注入或衰老的小鼠，我们证明了SREBP2反式激活microRNA-92a(miR-92a)是氧化应激诱导的。SREBP2诱导的miR-92a靶向内皮稳态的关键分子，包括Sirtuin 1、Krüppel-like factor2(KLF2)和KLF4，导致Nod样受体家族、含吡咯结构域3(NLRP3)的炎症小体激活和eNOS抑制。在EC特异性SREBP2转基因小鼠中，锁定核酸(LNA)修饰的反义miR-92a(LNA-92a)可以减轻炎症，改善血管扩张，并改善Ang II诱导的和衰老相关的动脉粥样硬化。在冠心病患者中，循环MIR-92a水平与EC依赖的血流介导的血管扩张呈负相关，与血清IL-1β水平呈正相关。我们的研究结果表明，SREBP2-miR-92a-炎症小体在氧化应激过程中加剧了内皮功能障碍。识别这一机制可能有助于诊断和/或治疗与氧化应激、先天免疫激活和内皮功能障碍相关的疾病。
Oxidative stress activates endothelial innate immunity and disrupts endothelial functions, including eNOS-derived NO bioavailability. Here, we postulated that oxidative stress induces sterol regulatory element binding protein 2 (SREBP2) and microRNA-92a (miR-92a), which in turn activate endothelial innate immune response, leading to dysfunctional endothelium. Using cultured endothelial cells (ECs) challenged by diverse oxidative stresses, hypercholesterolemic zebrafish, and Ang II-infused or aged mice, we demonstrated that SREBP2 transactivation of microRNA-92a (miR-92a) is oxidative stress-inducible. The SREBP2-induced miR-92a targets key molecules in endothelial homeostasis, including Sirtuin 1, Krüppel-like factor 2 (KLF2), and KLF4, leading to NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation and eNOS inhibition. In EC-specific SREBP2 transgenic mice, locked nucleic acid (LNA)-modified antisense miR-92a (LNA-92a) attenuates inflammasome, improves vasodilation, and ameliorates Ang II-induced and aging-related atherogenesis. In patients with coronary artery disease, the level of circulating miR-92a is inversely correlated with EC-dependent, flow-mediated vasodilation and is positively correlated with serum level of IL-1β. Our findings suggest that SREBP2-miR-92a-inflammasome exacerbates endothelial dysfunction during oxidative stress. Identification of this mechanism may help in diagnosis and/or treatment of disorders associated with oxidative stress, innate immune activation, and endothelial dysfunction.