Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
Atherosclerosis. 2022 Apr;347:1-16. doi: 10.1016/j.atherosclerosis.2022.02.025. Epub 2022 Mar 1.
Oxidative stress and abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) influence atherosclerosis formation and development. Oxidative stress significantly influences the abnormal proliferation and migration of VSMCs, and nuclear factor erythroid 2-related factor 2 (Nrf2) is a major antioxidant factor. However, the precise function of Nrf2 in the regulation of abnormal proliferation and migration of VSMCs and atherosclerosis is unclear.
We investigated the proliferation and migration of VSMCs in atherosclerosis in male Apoe and ApoeNrf2 mice fed a high-fat diet for 12 weeks. In cultured mouse VSMCs, we studied the effect of Nrf2 on ox-LDL-stimulated proliferation and migration by using siRNA treatment to silence Nrf2. We then performed dual luciferase reporter and immunoprecipitation assays to study the interaction between Nrf2 and the promoter sequence of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1).
Our results demonstrate that Nrf2 expression levels were increased in the aorta and VSMCs of mice in the atherosclerosis model group compared with the control group. We also provide evidence that Nrf2 deficiency attenuated atherosclerotic plaque burden, diminished proliferation, and migration of VSMCs but enhanced VSMC-specific marker gene expression in vitro and in vivo. This is related to Nrf2 binding to the promoter sequence of LOX-1. Furthermore, Nrf2 downregulation contributes to restrain both transcriptional and translational activities of LOX-1.
Together, our data indicate that Nrf2 insufficiency is linked to attenuation of atherosclerosis, and could diminish the pathological process by blunting LOX-1-mediated proliferation and migration of VSMCs.
氧化应激和血管平滑肌细胞（VSMC）的异常增殖和迁移影响动脉粥样硬化的形成和发展。氧化应激显著影响 VSMC 的异常增殖和迁移，核因子红细胞 2 相关因子 2（Nrf2）是主要的抗氧化因子。然而，Nrf2 在调节 VSMC 异常增殖和迁移以及动脉粥样硬化中的精确功能尚不清楚。
我们研究了高脂饮食喂养 12 周的 Apoe 和 ApoeNrf2 雄性小鼠动脉粥样硬化中 VSMC 的增殖和迁移。在培养的小鼠 VSMC 中，我们通过使用 siRNA 处理沉默 Nrf2 来研究 Nrf2 对 ox-LDL 刺激的增殖和迁移的影响。然后，我们进行了双荧光素酶报告和免疫沉淀测定，以研究 Nrf2 与凝集素样氧化型低密度脂蛋白受体-1（LOX-1）启动子序列之间的相互作用。
我们的结果表明，与对照组相比，动脉粥样硬化模型组小鼠主动脉和 VSMC 中的 Nrf2 表达水平增加。我们还提供了证据表明，Nrf2 缺乏减弱了动脉粥样硬化斑块负担，减少了 VSMC 的增殖和迁移，但增强了 VSMC 特异性标记基因的表达，无论是在体内还是体外。这与 Nrf2 与 LOX-1 启动子序列结合有关。此外，Nrf2 的下调有助于抑制 LOX-1 的转录和翻译活性。
综上所述，我们的数据表明，Nrf2 不足与动脉粥样硬化的减轻有关，并通过减弱 LOX-1 介导的 VSMC 增殖和迁移来减少病理过程。
