Abdominal aortic aneurysm (AAA) is a life-threatening condition, but effective medications to prevent its progression and rupture are currently lacking. The nuclear receptor pregnane-X-receptor (PXR) plays a crucial role in vascular homeostasis. However, the role of PXR in AAA development remains unknown. We first detected the PXR expression in human and murine AAA tissues by RT-qPCR and Western blot. To investigate the potential role of PXR in the development of AAA, we used adeno-associated virus-mediated overexpression of PXR and pharmacological activation of PXR by ginkgolide A (GA) in mouse AAA models induced by both angiotensin II (AngII) and calcium phosphate [Ca3(PO4)2]. The underlying mechanism was further explored using RNA-sequencing and molecular biological analyses. We found a significant decrease in both mRNA and protein levels of PXR in both human and murine aortic smooth muscle cells from AAA tissues, accompanied with phenotypic switching of vascular smooth muscle cell and increased oxidative stress. PXR overexpression in abdominal aortas and GA treatment successfully suppressed AAA formation in both mouse AAA models. RNA-sequencing data revealed that PXR activation inhibited gamma-aminobutyric acid type A receptor subunit alpha3 (GABRA3) expression. Additional mechanistic studies identified that PXR suppressed AAA through mitigating GABRA3-induced reactive oxygen species (ROS) generation and subsequent phosphorylation of c-Jun N-terminal kinase (JNK). Interestingly, p-JNK was found to induce ubiquitin-proteasome degradation of PXR. In summary, our data unveiled, for the first time, the protective role of PXR against AAA pathogenesis by inhibiting oxidative stress. These findings suggested PXR as a promising therapeutic target for AAA.

中文翻译：

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核受体 pregnane-X 受体的激活通过抑制氧化应激来预防腹主动脉瘤


腹主动脉瘤 （AAA） 是一种危及生命的疾病，但目前缺乏防止其进展和破裂的有效药物。核受体孕烷-X 受体 （PXR） 在血管稳态中起着至关重要的作用。然而，PXR 在 AAA 开发中的作用仍然未知。我们首先通过 RT-qPCR 和 Western blot 检测了人和小鼠 AAA 组织中的 PXR 表达。为了研究 PXR 在 AAA 发展中的潜在作用，我们在血管紧张素 II （AngII） 和磷酸钙 [Ca3 （PO4） 2] 诱导的小鼠 AAA 模型中使用了腺相关病毒介导的 PXR 过表达和银杏内酯 A （GA） 对 PXR 的药理学激活。使用 RNA 测序和分子生物学分析进一步探索了潜在机制。我们发现 AAA 组织中人和小鼠主动脉平滑肌细胞中 PXR 的 mRNA 和蛋白质水平显着降低，伴随着血管平滑肌细胞的表型转换和氧化应激增加。在两种小鼠 AAA 模型中，腹主动脉中的 PXR 过表达和 GA 处理都成功抑制了 AAA 的形成。RNA 测序数据显示 PXR 激活抑制 γ-氨基丁酸 A 型受体亚基 α3 （GABRA3） 表达。其他机制研究发现，PXR 通过减轻 GABRA3 诱导的活性氧 （ROS） 生成和随后的 c-Jun N 末端激酶 （JNK） 磷酸化来抑制 AAA。有趣的是，发现 p-JNK 诱导 PXR 的泛素-蛋白酶体降解。总之，我们的数据首次揭示了 PXR 通过抑制氧化应激对 AAA 发病机制的保护作用。这些发现表明 PXR 是 AAA 的一个有前途的治疗靶点。