ADAR1 in abdominal aortic aneurysm

摘要/摘要 腹主动脉瘤(AAA)是一种缺乏药物治疗的潜在致命性疾病。腹主动脉壁 炎症和随后的细胞外基质(ECM)蛋白的降解，特别是弹性蛋白的断裂， 是AAA发生发展的决定性因素。血管炎症，特别是巨噬细胞 活化和炎症性SMC表型，导致蛋白水解酶的产生，破坏细胞外基质 动态平衡导致血管壁变弱，从而形成AAA。然而，有一个关键的问题 关于控制血管炎症的机制(S)或关键因素(S)的认识差距 ECM失调。我们令人兴奋的初步数据表明，作用于RNA1(ADAR1)的腺苷脱氨酶 在诱导炎性SMC表型、巨噬细胞活化和AAA形成中起核心作用。 小鼠缺乏ADAR1(ADAR1/-)可显著减少AAA的形成(弹性蛋白断裂减少 和改善的动脉壁完整性)。ADAR1基因敲除或敲除也抑制炎症的SMC 表型和巨噬细胞活化。因此，ADAR1基因敲除抑制了 修复过程中SMC炎症表型标志物基质金属蛋白酶-2和9(MMP2/9)的表达 可收缩的SMC标志物。此外，当ADAR1被删除时，经典的MΦ激活被阻断。此外， ADAR1的表达与人类患者动脉瘤的形成有关。这些数据有力地支持了 ADAR1诱导炎症SMC表型和巨噬细胞激活的新假说，导致 血管炎症、弹性蛋白断裂，从而形成AAA。使用主要的老鼠和人类 SMC，体内ADAR1 SMC和巨噬细胞特异性基因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ADRA1 通过其编辑和非编辑功能促进MMP2/9的制作和活动；和2)建立 ADAR1调节MΦ激活的机制；以及3)决定SMC或髓系特异性缺失 ADAR1抑制AAA的形成。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可能促进我们的 了解AAA的形成并最终导致开发有效治疗的新策略 来治疗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.