BACKGROUND:Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy, likely due to the limited understanding of the mechanisms underlying AAA development and progression. Activating transcription factor (ATF) 3 has been increasingly recognized as a key regulator of cardiovascular diseases. However, the role of ATF3 (activating transcription factor 3) in AAA development and progression remains elusive.METHODS:Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline or Ang II (angiotensin II)–induced AAA mice, and ATF3 was identified as the potential key gene for AAA development. To examine the role of ATF3 in AAA development, vascular smooth muscle cell–specific ATF3 knockdown or overexpressed mice by recombinant adenoassociated virus serotype 9 vectors carrying ATF3, or shRNA-ATF3 with SM22α (smooth muscle protein 22-α) promoter were used in Ang II (angiotensin II)–induced AAA mice. In human and murine vascular smooth muscle cells, gain or loss of function experiments were performed to investigate the role of ATF3 in vascular smooth muscle cell proliferation and apoptosis.RESULTS:In both Ang II–induced AAA mice and patients with AAA, the expression of ATF3 was reduced in aneurysm tissues but increased in aortic lesion tissues. The deficiency of ATF3 in vascular smooth muscle cell promoted AAA formation in Ang II–induced AAA mice. PDGFRB (platelet-derived growth factor receptor β) was identified as the target of ATF3, which mediated vascular smooth muscle cell proliferation in response to TNF-alpha (tumor necrosis factor-α) at the early stage of AAA. ATF3 suppressed the mitochondria-dependent apoptosis at the advanced stage by upregulating its direct target BCL2. Our chromatin immunoprecipitation results also demonstrated that the recruitment of NFκB1 and P300/BAF/H3K27ac complex to the ATF3 promoter induces ATF3 transcription via enhancer activation. NFKB1 inhibitor (andrographolide) inhibits the expression of ATF3 by blocking the recruiters NFKB1 and ATF3-enhancer to the ATF3-promoter region, ultimately leading to AAA development.CONCLUSIONS:Our results demonstrate a previously unrecognized role of ATF3 in AAA development and progression, and ATF3 may serve as a novel therapeutic and prognostic marker for AAA.

中文翻译：

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时空 ATF3 表达决定腹主动脉瘤中 VSMC 的命运

背景：腹主动脉瘤 (AAA) 是一种灾难性疾病，几乎没有有效的治疗方法，这可能是由于对 AAA 发生和进展的机制了解有限。激活转录因子 (ATF) 3 越来越被认为是心血管疾病的关键调节因子。然而，ATF3（激活转录因子 3）在 AAA 发生和进展中的作用仍然难以捉摸。 方法：对从盐水或 Ang II（血管紧张素 II）诱导的 AAA 小鼠中分离的主动脉进行全基因组 RNA 测序分析，并对 ATF3 进行分析。被确定为AAA发育的潜在关键基因。为了研究 ATF3 在 AAA 发育中的作用，使用携带 ATF3 的重组腺相关病毒血清型 9 载体或带有 SM22α（平滑肌蛋白 22-α）启动子的 shRNA-ATF3 来敲除血管平滑肌细胞特异性 ATF3 或过表达小鼠。 II（血管紧张素 II）诱导的 AAA 小鼠。在人和小鼠血管平滑肌细胞中，进行了功能获得或丧失实验，以研究 ATF3 在血管平滑肌细胞增殖和凋亡中的作用。 结果：在 Ang II 诱导的 AAA 小鼠和 AAA 患者中， ATF3在动脉瘤组织中减少，但在主动脉病变组织中增加。血管平滑肌细胞中ATF3的缺乏促进了Ang II诱导的AAA小鼠中AAA的形成。 PDGFRB（血小板源性生长因子受体β）被确定为ATF3的靶标，ATF3在AAA早期响应TNF-α（肿瘤坏死因子-α）介导血管平滑肌细胞增殖。 ATF3 通过上调其直接靶标 BCL2 来抑制晚期线粒体依赖性细胞凋亡。我们的染色质免疫沉淀结果还表明，将 NFκB1 和 P300/BAF/H3K27ac 复合物募集至 ATF3 启动子可通过增强子激活诱导 ATF3 转录。 NFKB1 抑制剂（穿心莲内酯）通过阻断 ATF3 启动子区域的招募因子 NFKB1 和 ATF3 增强子来抑制 ATF3 的表达，最终导致 AAA 的发展。 结论：我们的结果表明 ATF3 在 AAA 的发展和进展中具有以前未被认识到的作用，并且ATF3 可作为 AAA 的新型治疗和预后标志物。