Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function
Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function
复制标题
Nrf-2信号通过调节血管平滑肌细胞表型和功能抑制颅内动脉瘤的形成和进展
DOI：
10.1186/s12974-019-1568-3
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发表时间：
2019-10-04
影响因子：
9.3
通讯作者：
Zhu, Wei
中科院分区：
文献类型：
--
作者：
Shi, Yuan;Li, Sichen;Zhu, Wei
氧化应激和血管平滑肌细胞（VSMC）表型调节影响颅内动脉瘤（IA）的形成和进展。氧化应激在表型转换中起着重要作用，而核因子红系2相关因子2 （Nrf-2）是主要的抗氧化系统之一。不幸的是，在IA发病过程中，我们对Nrf-2信号如何影响VSMC表型开关知之甚少。方法研究Nrf-2激活对弹性酶诱导大鼠IA模型形成和发展的影响。我们还建立了过氧化氢（H2O2）诱导的VSMC氧化损伤模型。然后，我们在体外分析了Nrf-2激活或抑制设置下VSMC表型的变化。检测VSMCs的增殖、迁移能力和凋亡率。最后，我们测量了Nrf-2下游抗氧化酶和炎症细胞因子的表达水平。结果Nrf-2激活可抑制体内IA的形成和进展。我们证实了Nrf-2核易位和VSMC从收缩表型到合成表型的转换。活化Nrf-2抑制H2O2增强的细胞增殖、迁移能力和凋亡率。定量实时聚合酶链反应（PCR）和western blot分析显示，Nrf-2的激活促进了抗氧化酶和vsmc特异性标记基因的表达，但降低了促炎细胞因子的水平。结论Nrf-2通过阻止VSMCs向合成表型转变，对IA发育具有保护作用。
Background Oxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation influence intracranial aneurysm (IA) formation and progression. Oxidative stress plays an important role in phenotype switching, and nuclear factor erythroid 2-related factor 2 (Nrf-2) is one of the main antioxidant systems. Unfortunately, little is known about how Nrf-2 signaling influences VSMC phenotype switches during IA pathogenesis. Methods We examined the effect of Nrf-2 activation IA on formation and progression in an elastase-induced rat IA model. We also developed a hydrogen peroxide (H2O2)-induced VSMC oxidative damage model. Then, we analyzed VSMC phenotype changes in the setting of Nrf-2 activation or inhibition in vitro. The proliferation, migration ability, and apoptosis rate of VSMCs were tested. Lastly, we measured the expression levels of antioxidant enzymes and inflammatory cytokines downstream of Nrf-2. Results Nrf-2 activation suppressed IA formation and progression in vivo. We confirmed Nrf-2 nuclear translocation and a VSMC switch from the contractile to synthetic phenotype. Nrf-2 activation inhibited the proliferation, migratory ability, and apoptosis rate enhanced by H2O2. Quantitative real-time polymerase chain reaction (PCR) and western blot analysis revealed that Nrf-2 activation promoted antioxidant enzymes and VSMC-specific marker gene expressions but decreased pro-inflammatory cytokine levels. Conclusion These results suggest that Nrf-2 exerts protective effects against IA development by preventing VSMCs from changing to a synthetic phenotype.