ADAR1 in abdominal aortic aneurysm

总结/摘要 腹主动脉瘤（AAA）是一种缺乏药物治疗的潜在致死性疾病。主动脉壁 炎症和随后的细胞外基质（ECM）蛋白的降解，特别是弹性蛋白断裂， 是AAA发展的决定性因素。血管炎症，特别是巨噬细胞 激活和炎性SMC表型，导致产生破坏ECM的蛋白水解酶 体内平衡导致血管壁变弱，从而形成AAA。然而，有一个关键的 关于控制血管炎症和炎症的机制或关键因素的知识差距 ECM失调。我们令人兴奋的初步数据表明，腺苷脱氨酶作用于RNA 1（ADAR 1）， 在诱导炎性SMC表型、巨噬细胞活化和AAA形成中起重要作用。 小鼠中的ADAR 1缺陷（ADAR 1 +/-）显著减弱AAA形成（弹性蛋白断裂减少 和改善的动脉壁完整性）。ADAR 1敲除或敲除也抑制炎性SMC 表型和巨噬细胞活化。因此，ADAR 1敲低抑制了 恢复期SMC中的炎症表型标志物包括基质金属蛋白酶2和9（MMP 2/9）， 收缩性SMC标志物。此外，当ADAR 1缺失时，经典的MΦ激活被阻断。此外，委员会认为， ADAR 1表达与人类患者动脉瘤形成相关。这些数据有力地支持了 ADAR 1诱导炎性SMC表型和巨噬细胞活化的新假设，导致 血管炎症、弹性蛋白断裂，并因此形成AAA。使用原代小鼠和人类 SMC，体内ADAR 1 SMC和巨噬细胞特异性敲除小鼠模型结合分子， 细胞，组织学和药理学方法，我们将1）确定ADRA 1 通过其编辑和非编辑职能促进MMP 2/9的制作和活动;以及2）建立 ADAR 1调节MΦ活化的机制;以及3）确定SMC或骨髓特异性缺失是否 ADAR 1减弱AAA形成。成功完成拟议的研究将建立新的 调节SMC炎症表型和血管炎症的机制，这可能会促进我们的研究。 了解AAA的形成，并最终导致开发有效疗法的新策略 治疗AAA。

Summary/Abstract Abdominal aortic aneurysm (AAA) is a potentially lethal disease that lacks pharmacological treatment. Aortic wall inflammation and subsequent degradation of extracellular matrix (ECM) proteins, especially the elastin breakage, are the determining factors for the development of AAA. Vascular inflammation, particularly macrophage activation and inflammatory SMC phenotype, causes the production of proteolytic enzymes that disrupt ECM homeostasis leading to a weakened vessel wall and consequently AAA formation. However, there is a critical knowledge gap concerning the mechanism(s) or key factor(s) controlling both the vascular inflammation and the ECM dysregulation. Our exciting preliminary data indicate that adenosine deaminase acting on RNA 1 (ADAR1) plays a central role in the induction of inflammatory SMC phenotype, macrophage activation, and AAA formation. ADAR1 deficiency (ADAR1+/-) in mice significantly attenuates AAA formation (with decreased elastin breakage and improved artery wall integrity). ADAR1 knockdown or knockout also inhibits the inflammatory SMC phenotype and macrophage activation. Consequently, ADAR1 knockdown inhibits the expression of inflammation phenotype markers including matrix metalloproteinase-2 and 9 (MMP2/9) in SMCs while restoring contractile SMC markers. In addition, the classical MΦ activation is blocked when ADAR1 is deleted. Moreover, ADAR1 expression is associated with aneurysm formation in human patients. These data strongly support a novel hypothesis that ADAR1 induces inflammatory SMC phenotype and macrophage activation, leading to vascular inflammation, elastin breakage, and consequently AAA formation. Using primary mouse and human SMCs, in vivo ADAR1 SMC- and macrophage-specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) determine the mechanisms by which ADRA1 promotes MMP2/9 production and activities through its editing and non-editing function; and 2) establish the mechanism by which ADAR1 regulates MΦ activation; and 3) determine if SMC- or myeloid-specific deletion of ADAR1 attenuates AAA formation. Successful completion of the proposed studies will establish novel mechanisms regulating SMC inflammatory phenotype and vascular inflammation, which are likely to advance our understanding of the AAA formation and ultimately lead to novel strategies for developing effective therapeutics to treat AAA.