Background:Metabolic disorder increases the risk of abdominal aortic aneurysm (AAA). NRs (nuclear receptors) have been increasingly recognized as important regulators of cell metabolism. However, the role of NRs in AAA development remains largely unknown.Methods:We analyzed the expression profile of the NR superfamily in AAA tissues and identified NR1D1 (NR subfamily 1 group D member 1) as the most highly upregulated NR in AAA tissues. To examine the role of NR1D1 in AAA formation, we used vascular smooth muscle cell (VSMC)–specific, endothelial cell–specific, and myeloid cell–specific conditional Nr1d1 knockout mice in both AngII (angiotensin II)– and CaPO₄-induced AAA models.Results:Nr1d1 gene expression exhibited the highest fold change among all 49 NRs in AAA tissues, and NR1D1 protein was upregulated in both human and murine VSMCs from AAA tissues. The knockout of Nr1d1 in VSMCs but not endothelial cells and myeloid cells inhibited AAA formation in both AngII- and CaPO₄-induced AAA models. Mechanistic studies identified ACO2 (aconitase-2), a key enzyme of the mitochondrial tricarboxylic acid cycle, as a direct target trans-repressed by NR1D1 that mediated the regulatory effects of NR1D1 on mitochondrial metabolism. NR1D1 deficiency restored the ACO2 dysregulation and mitochondrial dysfunction at the early stage of AngII infusion before AAA formation. Supplementation with αKG (α-ketoglutarate, a downstream metabolite of ACO2) was beneficial in preventing and treating AAA in mice in a manner that required NR1D1 in VSMCs.Conclusions:Our data define a previously unrecognized role of nuclear receptor NR1D1 in AAA pathogenesis and an undescribed NR1D1-ACO2 axis involved in regulating mitochondrial metabolism in VSMCs. It is important that our findings suggest αKG supplementation as an effective therapeutic approach for AAA treatment.

中文翻译：

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核受体 NR1D1 通过靶向线粒体三羧酸循环酶顺乌头酸酶 2 调节腹主动脉瘤的发展

背景：代谢紊乱会增加腹主动脉瘤 (AAA) 的风险。NRs（核受体）越来越被认为是细胞代谢的重要调节剂。然而，NRs 在 AAA 发展中的作用在很大程度上仍然未知。方法：我们分析了 AAA 组织中 NR 超家族的表达谱，并将 NR1D1（NR 亚家族 1 组 D 成员 1）鉴定为 AAA 组织中上调最高的 NR。为了检查 NR1D1 在 AAA 形成中的作用，我们在 AngII（血管紧张素 II）和 CaPO ₄诱导的 AAA中使用了血管平滑肌细胞 (VSMC) 特异性、内皮细胞特异性和骨髓细胞特异性条件性Nr1d1敲除小鼠模型。结果：Nr1d1基因表达在 AAA 组织中的所有 49 个 NR 中表现出最高的倍数变化，并且 NR1D1 蛋白在来自 AAA 组织的人和鼠 VSMC 中均被上调。在 VSMC 中敲除Nr1d1而不是内皮细胞和骨髓细胞会抑制 AngII- 和 CaPO _{4中 AAA 的形成}-诱导的 AAA 模型。机理研究发现 ACO2（aconitase-2）是线粒体三羧酸循环的关键酶，是 NR1D1 反式抑制的直接靶标，介导 NR1D1 对线粒体代谢的调节作用。NR1D1 缺陷恢复了 AAA 形成前 AngII 输注早期的 ACO2 失调和线粒体功能障碍。补充 αKG（α-酮戊二酸，ACO2 的下游代谢产物）有利于以 VSMC 中需要 NR1D1 的方式预防和治疗小鼠 AAA。未描述的 NR1D1-ACO2 轴参与调节 VSMC 中的线粒体代谢。