Aim Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of intracellular adenosine level, and to investigate the underlying mechanisms. Methods and Results We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). Heterozygous deficiency of Adk protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of Adk in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. Metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation and AAA formation. Conclusion Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis.

中文翻译：

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腺苷激酶抑制通过 VSMC 炎症的表观遗传调节保护小鼠免受腹主动脉瘤的影响

目的 腹主动脉瘤（AAA）是一种常见的严重血管疾病，目前尚无有效的药物治疗方法。核苷腺苷在调节血管稳态中发挥着重要作用，这促使我们确定腺苷激酶（ADK）（一种腺苷代谢酶）是否通过控制细胞内腺苷水平来调节 AAA 的形成，并研究其潜在机制。方法和结果 我们在使用氯化钙 (CaCl2) 或输注血管紧张素 II (Ang II) 诱导的 AAA 小鼠模型中结合使用遗传和药理学方法来研究 ADK 在 AAA 发展中的作用。通过用腺病毒短发夹 RNA 敲低人血管平滑肌细胞 (VSMC) 中的 ADK 进行体外功能测定，并使用 RNA 测序、同位素示踪和染色质免疫沉淀定量聚合酶链反应研究 ADK 功能的分子机制。 ChIP-qPCR）。 Adk 杂合缺陷可保护小鼠免受 CaCl2 和 Ang II 诱导的 AAA 形成。此外，VSMC 中 Adk 的特异性敲除可阻止 Ang II 诱导的 AAA 形成，这可通过减少主动脉细胞外弹性蛋白碎片、新血管形成和主动脉炎症来证明。从机制上讲，VSMC 中的 ADK 敲低显着抑制了与 AAA 形成相关的炎症基因的表达，并且这些作用与腺苷受体无关。代谢流和 ChIP-qPCR 结果表明，VSMC 中 ADK 敲低可减少 S-腺苷甲硫氨酸 (SAM) 依赖性转甲基化，从而减少 H3K4me3 与炎症、血管生成和细胞外弹性蛋白断裂相关基因启动子区域的结合。此外，ADK 抑制剂 ABT702 可以保护小鼠免受 CaCl2 诱导的主动脉炎症、细胞外弹性蛋白断裂和 AAA 形成。结论 我们的研究结果揭示了 ADK 抑制通过对与 AAA 发病机制相关的关键炎症基因进行表观遗传调节来减轻 AAA 的新作用。