ANK Deficiency-Mediated Cytosolic Citrate Accumulation Promotes Aortic Aneurysm.

IF 16.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-11-08 DOI:10.1161/CIRCRESAHA.124.325152

Hao Wu, Zhiqing Li, Liu Yang, Lin He, Hao Liu, Shiyu Yang, Qinfeng Xu, Yanjie Li, Wenqiang Li, Yiran Li, Ze Gong, Yicong Shen, Xueyuan Yang, Jiaqi Huang, Fang Yu, Li Junming Zhu, Luyang Sun, Yi Fu, Wei Kong

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Abstract

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.

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ANK缺陷介导的细胞膜柠檬酸盐积累会诱发主动脉瘤

背景：柠檬酸盐代谢和转运紊乱在各种病症中起着重要作用。然而，人们对血管柠檬酸盐调控及其在主动脉瘤（AA）发展中的潜在作用仍然知之甚少：方法：采用质谱法进行非靶向代谢组学研究，以确定小鼠 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体ANK（渐进性强直蛋白）在AA发病中的作用，研究人员在血管紧张素II（Angiotensin II）和CaPO4诱导的AA模型中使用了血管平滑肌细胞（VSMC）特异性ANK基因敲除小鼠：结果：人和小鼠动脉瘤组织中的柠檬酸盐都异常增加，这与VSMC中柠檬酸盐膜转运体ANK的下调有关。在 Ang II 和 CaPO4 诱导的 AA 模型中，敲除 VSMC 中的 ANK 会促进 AA 的形成，而过表达 ANK 则会抑制动脉瘤的发展。从机理上讲，VSMCs 中 ANK 的缺乏会导致柠檬酸盐在细胞膜上的异常积累，柠檬酸盐被裂解为乙酰辅酶 A，从而加强了 H3K23、H3K27 和 H4K5 处的组蛋白乙酰化。靶标下的裂解和标记分析进一步确定，ANK 缺乏诱导的组蛋白乙酰化激活了血管内皮细胞炎症基因的转录，从而在动脉瘤疾病期间促进了与柠檬酸盐相关的促炎血管内皮细胞表型。因此，抑制柠檬酸盐裂解为乙酰辅酶A可降低VSMCs中炎症基因的表达，并限制ANK缺乏症加重的AA形成：我们的研究确定了 ANK 缺乏症诱导的细胞膜柠檬酸盐积累在 AA 发病中的致病作用，以及一种未被描述的与柠檬酸盐相关的促炎 VSMC 表型。针对 ANK 介导的柠檬酸盐转运可能成为 AA 的一种新型诊断和治疗策略。

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来源期刊

Circulation research 医学-外周血管病

CiteScore

29.60

自引率

2.00%

发文量

535

审稿时长

3-6 weeks

期刊介绍： Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.

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