Dedicator of cytokinesis 2 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 浸润和炎症性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，胞质分裂奉献因子2(DOCK2)在 在诱导炎性SMC表型和AAA形成中起中心作用。DOCK2缺乏(DOCK2-/-) 显著减少小鼠AAA的形成(减少弹性蛋白断裂和改善动脉壁 完整性)，并减少炎症性SMC表型的诱导。因此，DOCK2-/-抑制了 单核细胞趋化蛋白-1和基质金属蛋白酶-2在血管内皮细胞中的表达 同时恢复收缩的SMC标志物。一直以来，动脉瘤动脉中层的巨噬细胞浸润 在DOCK2-/-小鼠体内被阻断。此外，DOCK2的表达与人类动脉瘤的形成有关 病人。这些数据有力地支持了DOCK2诱导炎性SMC表型的新假设 导致血管炎症、弹性蛋白断裂，从而形成AAA。使用主鼠标和 人SMC、体内DOCK2 SMC-、巨噬细胞和T细胞特异性基因敲除小鼠模型 分子、细胞、组织和药理学方法，我们将1)通过以下方式确定其机制 哪种DOCK2调节炎症的SMC表型；以及2)检验DOCK2促进AAA的假设 在体内通过刺激炎症的SMC表型形成。圆满完成拟议的研究 将建立调控SMC炎症表型和血管炎症的新机制，这些机制包括 可能会促进我们对AAA形成的理解，并最终导致新的发展战略 治疗AAA的有效疗法。

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 infiltration 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 dedicator of cytokinesis 2 (DOCK2) plays a central role in the induction of inflammatory SMC phenotype and AAA formation. DOCK2 deficiency (DOCK2-/-) in mice significantly attenuates AAA formation (with decreased elastin breakage and improved artery wall integrity) and diminishes the induction of inflammatory SMC phenotype. Consequently, DOCK2-/- inhibits the expression of monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-2 (MMP2) in SMCs while restoring contractile SMC markers. Consistently, the macrophage infiltration in aneurysm arterial media is blocked in DOCK2-/- mice. Moreover, DOCK2 expression is associated with aneurysm formation in human patients. These data strongly support a novel hypothesis that DOCK2 induces inflammatory SMC phenotype leading to vascular inflammation, elastin breakage, and consequently AAA formation. Using primary mouse and human SMCs, in vivo DOCK2 SMC-, macrophage-, and T cell- specific knockout mouse models combining with molecular, cellular, histological, and pharmacological approaches, we will 1) determine the mechanisms by which DOCK2 regulates inflammatory SMC phenotype; and 2) test the hypothesis that DOCK2 promotes AAA formation by stimulating inflammatory SMC phenotype in vivo. 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.