SETDB2 regulates Abdominal Aortic Aneurysms

项目总结/摘要 在腹主动脉瘤（AAA）形成过程中，病理性血管重塑由巨噬细胞驱动 巨噬细胞介导的AAA发生的机制尚不清楚。在 在正常的主动脉壁中，基质金属蛋白酶（MMPs）之间存在平衡，其功能是打破 和基质金属蛋白酶组织抑制剂（TIMPs），其阻止 基质金属蛋白酶在主动脉壁上。然而，在病理环境中，MMP和TIMP之间发生不平衡 有利于MMP活性，导致AAA的发展。虽然表观遗传机制已被证明， 尽管这些表观遗传途径在组织中调节Mφ表型，但这些表观遗传途径在主动脉组织中的调节仍是未知的。 我们的初步数据表明，SETDB 2，一种选择性甲基化组蛋白3的组蛋白甲基转移酶， 在赖氨酸9处，降低基因转录，并在鼠和人AAA Mφ中增加。此外，我们发现 JAK 1/STAT 3信号通路可调节主动脉Mφ中Setdb 2的表达。考虑到这些发现，我们假设 SETDB 2通过JAK/STAT信号通路驱动AAA形成，该信号通路使Mφ向 TIMP产生减少，有利于不受调节的MMP和AAA的发展。这一假设将是 1）确定JAK/STAT/SETDB 2介导的机制 调节人和鼠AAAs中Mφ特异性Timp 1 -3表达2）检查治疗功效 M φ特异性JAK/STAT/SETDB 2抑制AAA扩增的作用。在这种转化方法中，我们的数据将为 开发有前景的预防性治疗剂的途径，旨在细胞特异性靶向 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.