ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype
ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype
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DOI：
10.1161/circresaha.117.310692
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发表时间：
2017-08-18
影响因子：
20.1
通讯作者：
Gamble, Jennifer R.
中科院分区：
文献类型：
--
作者：
Liu, Renjing;Lo, Lisa;Gamble, Jennifer R.
基本原理：胸主动脉瘤（TAA）是一种潜在的致命疾病，可影响所有年龄段的个体。TAA可能因突然发生危及生命的夹层或破裂而复杂化。导致TAA形成的潜在机制，特别是在非综合征特发性患者组中，还不清楚。因此，需要鉴定参与TAA发病机制的新基因和靶点，以帮助预防和逆转疾病表型。目的：在这里，我们探索ARHGAP 18，一种由平滑肌细胞（SMCs）表达的新型Rho GAP，在TAA发病机制中的作用。方法和结果：使用人类和小鼠的主动脉样本，我们报告说，ARHGAP 18水平显着降低SMC层的主动脉瘤。Arhgap 18全基因敲除（Arhgap 18-/-）小鼠在基础条件下表现出高度合成、蛋白水解和促炎性平滑肌表型，当用血管紧张素II激发时，与同窝对照组相比，TAA的发生频率和严重程度增加。染色质免疫沉淀研究显示，这种表型部分与在Arhgap 18缺陷型SMC中MMP 2和TNF-α启动子处H3 K4 me 3的强烈富集和H3 K27 me 3的耗尽相关。我们进一步表明，在Arhgap 18（-/-）小鼠中TAA的形成与Akt活化的丧失有关。在Arhgap 18（-/-）小鼠中观察到的异常SMC表型可以部分获救的mTORC 1抑制剂雷帕霉素，减少合成和促炎表型的Arhgap 18缺陷SMC.Conclusion的药理学治疗：我们已经确定ARHGAP 18作为一种新的保护基因对TAA的形成，并确定了一个额外的目标，为未来发展的治疗，以限制TAA的发病机制。
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-alpha 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.