BACKGROUND Disturbed metabolism and transport of citrate play significant roles in various pathologies. However, vascular citrate regulation and its potential role in aortic aneurysm (AA) development remain poorly understood. METHODS Untargeted metabolomics by mass spectrometry was applied to identify upregulated metabolites of the tricarboxylic acid cycle in AA tissues of mice. To investigate the role of citrate and its transporter ANK (progressive ankylosis protein) in AA development, vascular smooth muscle cell (VSMC)-specific Ank-knockout mice were used in both Ang II (angiotensin II)- and CaPO4-induced AA models. RESULTS Citrate was abnormally increased in both human and murine aneurysmal tissues, which was associated with downregulation of ANK, a citrate membrane transporter, in VSMCs. The knockout of Ank in VSMCs promoted AA formation in both Ang II- and CaPO4-induced AA models, while its overexpression inhibited the development of aneurysms. Mechanistically, ANK deficiency in VSMCs caused abnormal cytosolic accumulation of citrate, which was cleaved into acetyl coenzyme A and thus intensified histone acetylation at H3K23, H3K27, and H4K5. Cleavage under target and tagmentation analysis further identified that ANK deficiency-induced histone acetylation activated the transcription of inflammatory genes in VSMCs and thus promoted a citrate-related proinflammatory VSMC phenotype during aneurysm diseases. Accordingly, suppressing citrate cleavage to acetyl coenzyme A downregulated inflammatory gene expression in VSMCs and restricted ANK deficiency-aggravated AA formation. CONCLUSIONS Our studies define the pathogenic role of ANK deficiency-induced cytosolic citrate accumulation in AA pathogenesis and an undescribed citrate-related proinflammatory VSMC phenotype. Targeting ANK-mediated citrate transport may emerge as a novel diagnostic and therapeutic strategy in AA.

中文翻译：

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ANK 缺陷介导的胞质柠檬酸盐积累促进主动脉瘤。


背景 柠檬酸盐的代谢和运输紊乱在各种病理中起着重要作用。然而，血管柠檬酸盐调节及其在主动脉瘤 （AA） 发展中的潜在作用仍然知之甚少。方法 通过质谱法应用非靶向代谢组学鉴定小鼠 AA 组织中三羧酸循环的上调代谢物。为了研究柠檬酸盐及其转运蛋白 ANK （进行性强直蛋白） 在 AA 发展中的作用，血管平滑肌细胞 （VSMC） 特异性 Ank 敲除小鼠用于 Ang II （血管紧张素 II） 和 CaPO4 诱导的 AA 模型。结果 枸橼酸盐在人和小鼠动脉瘤组织中均异常增加，这与 VSMC 中柠檬酸盐膜转运蛋白 ANK 的下调有关。在 VSMC 中敲除 Ank 促进了 Ang II 和 CaPO4 诱导的 AA 模型中的 AA 形成，而其过表达抑制了动脉瘤的发展。从机制上讲，VSMC 中的 ANK 缺陷导致柠檬酸盐的异常胞质积累，柠檬酸盐被裂解成乙酰辅酶 A，从而在 H3K23、H3K27 和 H4K5 处加强组蛋白乙酰化。靶向和标记分析下的切割进一步发现，ANK 缺陷诱导的组蛋白乙酰化激活了 VSMCs 中炎症基因的转录，从而在动脉瘤疾病期间促进了柠檬酸盐相关的促炎 VSMC 表型。因此，抑制柠檬酸盐裂解乙酰辅酶 A 下调 VSMC 中的炎症基因表达并限制 ANK 缺陷加重的 AA 形成。结论 我们的研究确定了 ANK 缺陷诱导的胞质柠檬酸盐积累在 AA 发病机制和未描述的柠檬酸盐相关促炎性 VSMC 表型中的致病作用。 靶向 ANK 介导的柠檬酸盐转运可能成为 AA 中的一种新的诊断和治疗策略。