SETDB2 regulates Abdominal Aortic Aneurysms

项目摘要/摘要 在腹主动脉瘤(AAA)形成过程中，巨噬细胞驱动病理性血管重构。 (MφS)的侵袭，以及调节巨噬细胞介导的腹主动脉瘤发展的机制仍不清楚。在……里面 在正常的主动脉壁中，基质金属蛋白酶(MMPs)之间存在平衡，其功能是破坏 和基质金属蛋白酶(TIMPs)的组织抑制物，它们阻止了 主动脉壁上有基质金属蛋白。然而，在病理环境中，在MMP和TIMP之间发生不平衡 有利于基质金属蛋白酶的活性，导致腹主动脉瘤的发生。尽管表观遗传机制已被证明 在组织中调节M-φ的表型，但这些表观遗传途径在主动脉组织中的调节仍不清楚。 我们的初步数据确定SETDB2组蛋白甲基转移酶选择性甲基化组蛋白3 在小鼠和人AAA Mφ中，9位赖氨酸降低了基因转录，而增加了基因转录。此外，我们发现 JAK1/STAT3信号转导通路可能调节主动脉MφS的SET_2。 SETDB2通过JAK/STAT信号通路驱动AAA的形成，使MφS向 减少TIMP的产生，有利于不受调控的MMPs和AAA的发展。这一假设将是 通过以下具体目标进行研究：1)确定JAK/STAT/SETDB2介导的机制(S) 调节Mφ特异性TIMP1-3在人和小鼠AAA中的表达2)检测治疗效果 Mφ特异性JAK/STAT/SETDB2AAA扩增抑制作用的研究在这种转换方法中，我们的数据将为 以细胞特异性靶向为靶点的有前景的预防性治疗药物的发展方向 表观遗传酶，介导Mφ炎症，从而防止AAA扩张和破裂。

PROJECT SUMMARY/ABSTRACT During abdominal aortic aneurysm (AAA) formation, pathological vascular remodeling is driven by macrophage (Mφs) infiltration, and the mechanisms regulating macrophage-mediated AAA development remain undefined. In the normal aortic wall, a balance exists between matrix metalloproteinases (MMPs), which function to break down the aortic wall, and tissue inhibitors of matrix metalloproteinases (TIMPs), which prevent the actions of MMPs on the aortic wall. However, in a pathologic setting, an imbalance occurs between the MMPs and TIMPs in favor of MMP activity, resulting in AAA development. Although epigenetic mechanisms have been shown to regulate Mφ phenotype in tissues, the regulation of these epigenetic pathways in aortic tissue remains unknown. Our preliminary data identifies that SETDB2, a histone methyltransferase that selectively methylates histone 3 at lysine 9, decreases gene transcription and is increased in murine and human AAA Mφs. Further, we found that JAK1/STAT3 signaling may regulate Setdb2 in aortic Mφs. Considering these findings, we hypothesize that SETDB2 drives AAA formation through a JAK/STAT signaling pathway which shifts Mφs towards a decreased TIMP production, favoring unregulated MMPs and AAA development. This hypothesis will be investigated through the following specific aims: 1) Determine the JAK/STAT/SETDB2-mediated mechanism(s) that regulate Mφ-specific Timp1-3 expression in human and murine AAAs 2) Examine the therapeutic efficacy of Mφ-specific JAK/STAT/SETDB2 inhibition on AAA expansion. In this translational approach, our data will pave the way for the development of promising preventative therapeutic agents aimed at cell-specific targeting of epigenetic enzymes that mediate Mφ inflammation and thereby prevent AAA expansion and rupture.