JMJD3 Regulates Abdominal Aortic Aneurysm Expansion

项目摘要/摘要 腹主动脉瘤(Aaa)是一种潜在的致命性血管疾病，如果不及时治疗，病情可能会恶化。 到主动脉破裂，死亡率超过80%。同样令人担忧的是，目前还没有 可用于限制AAA生长的治疗方法，在很大程度上是由于对分子的缺乏了解 AAA发展的潜在机制。因此，迫切需要了解 治理AAA级扩张。AAA的一个重要特征是炎性巨噬细胞(Mφ)渗入 血管壁。我们提供了使用人类单细胞RNA测序和小鼠AAA模型的数据， 组蛋白去甲基酶，JMJD3，在主动脉瘤组织中升高MφS导致持续性炎症 M-φ表型，并增加了NF-κ-B炎性介质的产生。此外，使用人类细胞和我们的 在实验性小鼠AAA模型中，我们已经确定了干扰素-β(干扰素-β)通过JAK/ 信号转导和转录激活因子(STAT)机制诱导MφS的JMJD3。 导致我们的假设是干扰素/JAK/STAT信号直接增加了主动脉组织MφJmjd3的表达。S JMDJ3介导的表观遗传修饰驱动NFkB介导的炎症基因维持 主动脉Mφ的炎症表型，从而促进了腹主动脉瘤的发展。我们进一步假设Mφ 功能可通过单核细胞-Mφ靶向抑制JMJD3介导的表观遗传修饰来恢复 从而消退炎症，稳定AAA。这一假设将通过 目的1：阐明核因子κB介导的炎症基因表达的调控。 人和小鼠AAA单核细胞中的JMJD3/MφS。目的2：确定干扰素/JAK/STAT介导的 调节人和小鼠AAA中Mφ特异性Jmjd3表达的机制(S)。目标3：研究 M-φ靶向JMJD3抑制腹主动脉瘤扩张的疗效在这种翻译方法中，我们的 数据将为开发针对细胞特异性的有前途的预防性治疗药物铺平道路 以表观遗传酶为靶点，介导Mφ炎症，从而防止AAA扩张和 破裂。

PROJECT SUMMARY/ABSTRACT Abdominal aortic aneurysms (AAA) are a potentially lethal vascular disease that if left untreated, can progress to aortic rupture which has a mortality rate over 80%. Equally alarming, there are currently no medical therapies available to limit AAA growth, due in large part to a lack of understanding of the molecular mechanisms underlying AAA development. Thus, a critical need exists to understand the mechanisms that govern AAA expansion. One key hallmark of AAAs is inflammatory macrophage (Mφ) infiltration into the vascular wall. We present data using human single cell RNA sequencing and murine AAA models, that the histone demethylase, JMJD3, is increased in aortic aneurysm tissue Mφs resulting in a persistent inflammatory Mφ phenotype with increased production of NFκB inflammatory mediators. Further, using human cells and our experimental murine model of AAAs, we have identified that interferon-beta (IFNβ), via a janus kinase (JAK) / signal transducer and activator of transcription (STAT) mechanism induces JMJD3 in Mφs. These results have led to our hypothesis that IFN?/JAK/STAT signaling directly increases Jmjd3 expression in aortic tissue Mφs and JMDJ3-mediated epigenetic modifications drive NFkB-mediated inflammatory genes that maintain an aortic Mφ inflammatory phenotype, thereby promoting AAA development. We further postulate that Mφ function may be restored via monocyte-Mφ-targeted inhibition of the JMJD3-mediated epigenetic modifications resulting in the resolution of inflammation and AAA stabilization. This hypothesis will be investigated via the following specific aims: Aim 1: Elucidate the regulation of NFκB-mediated inflammatory gene expression by JMJD3 in human and murine AAA monocyte/Mφs. Aim 2: Determine the IFN?/JAK/STAT-mediated mechanism(s) that regulate Mφ-specific Jmjd3 expression in human and murine AAAs. Aim 3: Examine the therapeutic efficacy of Mφ-targeted JMJD3 inhibition on AAA expansion. In this translational approach, our data will pave the way for the development of promising preventive therapeutic agents aimed at cell-specific targeting of epigenetic enzymes that mediate Mφ inflammation and thereby prevent AAA expansion and rupture.