Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into mice, while EC-specific knockdown of Nrf2 was generated in mice. Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. Upon HCD feeding in mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.

中文翻译：

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Nrf2 的激活通过抑制内皮细胞炎症和脂质过氧化来抑制 ApoE−/− 小鼠的动脉粥样硬化


核红细胞 2 相关因子 2 (Nrf2) 是一种转录因子，在氧化应激和炎症的调节中发挥着重要作用。然而，内皮 Nrf2 在动脉粥样硬化形成中的作用尚未明确。此外，内皮Nrf2如何被激活以及Nrf2是否可以靶向预防和治疗动脉粥样硬化也尚未探讨。使用小鼠动脉粥样硬化主动脉的RNA测序和单细胞RNA测序分析来鉴定差异表达的基因。通过将腺相关病毒注射到小鼠体内，实现了 Nrf2 的内皮细胞 (EC) 特异性激活，同时在小鼠体内产生了 Nrf2 的 EC 特异性敲低。内皮炎症早在小鼠喂食高胆固醇饮食 (HCD) 后第 3 天就出现了，如 mRNA 水平、免疫染色和整体 mRNA 分析所示，而脂质过氧化 (LPO) 最终产物的免疫信号4 -羟基壬醛 (4-HNE)，在第 10 天开始增加。TNF-α、4-HNE 和erastin（LPO 诱导剂）通过增加 Nrf2 靶基因的 mRNA 和蛋白质表达来激活人 EC 中的 Nrf2 信号传导。内皮 Nrf2 的敲低会导致小鼠内皮炎症和 LPO 增加，并加速动脉粥样硬化。相比之下，Nrf2 的 EC 特异性激活和药理学激活均抑制内皮炎症、LPO 和动脉粥样硬化形成。当 HCD 喂养小鼠时，内皮炎症是最早发生的事件，随后是 LPO 的出现。 EC 特异性激活 Nrf2 可抑制动脉粥样硬化，而 EC 特异性敲低 Nrf2 会产生相反的效果。内皮 Nrf2 的药理学激活剂可能代表治疗动脉粥样硬化的一种新的治疗策略。