BACKGROUND:Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive.METHODS:Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell–specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl₂; 0.5 mol/L; 42 days).RESULTS:Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II– or CaCl₂-treated mice. Global or vascular smooth muscle cell–specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II– and CaCl₂-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process.CONCLUSIONS:Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.

中文翻译：

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LXRα通过UHRF1对miR-26b-3p的表观遗传修饰促进腹主动脉瘤形成

背景：腹主动脉瘤（AAA）是一种严重的主动脉疾病，目前尚无有效的药物治疗方法。由NR1H3基因编码的核激素受体 LXRα（肝 X 受体 α）是与多种血管病理相关的关键转录介质，但其在 AAA 中的作用仍然难以捉摸。 方法：通过对人和小鼠 AAA 基因表达的综合分析通过微阵列数据集，我们将NR1H3确定为调节 AAA 形成的候选基因。为了研究 LXRα 在 AAA 形成中的作用，我们在用血管紧张素 II（1000 ng·kg·min；28 天）或氯化钙诱导的 2 个 AAA 小鼠模型中使用了整体Nr1h3敲除小鼠和血管平滑肌细胞特异性Nr1h3敲除小鼠。 （CaCl ₂；0.5 mol/L；42 天）。结果：在 AAA 患者的主动脉以及血管紧张素 II 或 CaCl ₂治疗的小鼠的主动脉中观察到 LXRα 上调。在 2 个小鼠模型中，整体或血管平滑肌细胞特异性Nr1h3敲除抑制了 AAA 形成。 LXRα功能的丧失可防止细胞外基质变性、炎症和血管平滑肌细胞表型转换。通过转录组测序和染色质免疫沉淀测序的综合分析，将表观遗传主调控因子Uhrf1确定为LXRα的直接靶基因。在血管紧张素 II 和 CaCl ₂诱导的小鼠模型中，UHRF1（含有 PHD 和环指结构域的泛素样蛋白）持续增强了 AAA 发育的易感性。然后，我们使用 CUT&Tag（靶点下切割和标签化）、RRBS（简化代表性亚硫酸氢盐测序）和 ATAC-seq（转座酶可及染色质测序分析）在血管平滑肌中确定了 UHRF1 介导的基因的 CpG 甲基化状态和启动子可及性肌细胞，揭示 UHRF1 募集到 miR-26b 启动子导致 DNA 高甲基化，并伴有相对封闭的染色质状态，并导致 AAA 中 miR-26b 表达下调。关于临床意义，我们发现 miR-26b-3p 的低表达与 AAA 患者的高风险相关。维持 miR-26b-3p 表达可阻止 AAA 进展并减轻总体病理过程。结论：我们的研究揭示了 LXRα/UHRF1/miR-26b-3p 轴在 AAA 中的关键作用，并为 AAA 提供了潜在的生物标志物和治疗靶点。