Rationale: Thoracic aortic aneurysm (TAA) is a potentially lethal condition, which can affect individuals of all ages. TAA may be complicated by the sudden onset of life-threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the nonsyndromal idiopathic group of patients, are not well understood. Thus, identification of new genes and targets that are involved in TAA pathogenesis are required to help prevent and reverse the disease phenotype.

Objective: Here we explore the role of ARHGAP18, a novel Rho GAP expressed by smooth muscle cells (SMCs), in the pathogenesis of TAA.

Methods and Results: Using human and mouse aortic samples, we report that ARHGAP18 levels were significantly reduced in the SMC layer of aortic aneurysms. Arhgap18 global knockout (Arhgap18^−/−) mice exhibited a highly synthetic, proteolytic, and proinflammatory smooth muscle phenotype under basal conditions and when challenged with angiotensin II, developed TAA with increased frequency and severity compared with littermate controls. Chromatin immunoprecipitation studies revealed this phenotype is partly associated with strong enrichment of H3K4me3 and depletion of H3K27me3 at the MMP2 and TNF-α promoters in Arhgap18-deficient SMC. We further show that TAA formation in the Arhgap18^−/− mice is associated with loss of Akt activation. The abnormal SMC phenotype observed in the Arhgap18^−/− mice can be partially rescued by pharmacological treatment with the mTORC1 inhibitor rapamycin, which reduces the synthetic and proinflammatory phenotype of Arhgap18-deficient SMC.

Conclusion: We have identified ARHGAP18 as a novel protective gene against TAA formation and define an additional target for the future development of treatments to limit TAA pathogenesis.

理由：胸主动脉瘤（TAA）是一种潜在的致死性疾病，可影响各个年龄段的个体。威胁生命的解剖或破裂的突然发作可能会使TAA变得复杂。导致TAA形成的潜在机制，特别是在非综合征性特发性患者中，尚未得到很好的了解。因此，需要鉴定与TAA发病机理有关的新基因和靶标，以帮助预防和逆转疾病表型。

目的：在这里我们探讨由平滑肌细胞（SMC）表达的新型Rho GAP ARHGAP18在TAA发病机理中的作用。

方法和结果：使用人类和小鼠的主动脉样本，我们报告说，在主动脉瘤的SMC层中ARHGAP18水平显着降低。在基础条件下， Arhgap18整体基因敲除（ Arhgap18 ^{-/ -}）小鼠表现出高度合成，蛋白水解和促炎的平滑肌表型，当与血管紧张素II攻击时，与同窝对照相比，TAA的发生频率和严重性增加。染色质的免疫沉淀研究表明，该表型部分与Arhgap18中MMP2和TNF-α启动子的H3K4me3的强富集和H3K27me3的耗竭有关-SMC不足。我们进一步表明，在Arhgap18 ^-/-小鼠中TAA的形成与Akt激活的丧失有关。在Arhgap18 ^-/-小鼠中观察到的异常SMC表型可以通过mTORC1抑制剂雷帕霉素的药理治疗部分挽救，从而降低了Arhgap18缺陷型SMC的合成和促炎表型。

结论：我们已经将ARHGAP18鉴定为针对TAA形成的新型保护基因，并为限制TAA发病机理的治疗方法的未来发展确定了另一个目标。