Department of Clinical Laboratory, Laohekou No.1 Hospital.
Department of Pharmacy, Xiangyang Central Hospita, Affiliated Hospital of Hubei University of Arts and Science.
Tohoku J Exp Med. 2023 Sep 20;261(1):57-67. doi: 10.1620/tjem.2023.J048. Epub 2023 Jun 8.
Intracranial aneurysms are dilatations in the arteries that supply blood to the brain. Rupture of an intracranial aneurysm leads to a subarachnoid hemorrhage, which is fatal in about 50% of the cases. Microarray-based mRNA expression studies provide unbiased information about molecular mechanisms of intracranial aneurysm and the foundation for functional studies. In this study, by using a Gene Expression Omnibus (GEO) dataset, we identified distal-less homeobox 2 (DLX2) as a significantly upregulated gene in intracranial aneurysms and set to dissect its functional role and upstream mechanism. Here, we found that DLX2 expression was elevated in intracranial aneurysm patients. Silencing of DLX2 suppressed the proliferative capacity of human aortic vascular smooth muscle cells (HA-VSMC) and promoted their apoptosis. Moreover, loss of DLX2 promoted collagen I and collagen III and inhibited the levels of MMP2/9 and pro-inflammatory factors. Additionally, jumonji domain-containing protein 3 demethylase (JMJD3) promoted DLX2 expression by inhibiting H3K27me3 modification. Depletion of JMJD3 exerted the same function as DLX2 in vitro and in vivo, whereas overexpression of DLX2 in the presence of JMJD3 knockdown led to accentuated intracranial aneurysm progression and enhanced HA-VSMC survival. We conclude that JMJD3 promotes DLX2 expression through inhibition of H3K27me3 modification, thereby promoting intracranial aneurysm formation.
颅内动脉瘤是大脑供血动脉的扩张。颅内动脉瘤破裂会导致蛛网膜下腔出血，约有 50%的病例是致命的。基于微阵列的 mRNA 表达研究为颅内动脉瘤的分子机制和功能研究提供了无偏倚的信息。在这项研究中，我们通过使用基因表达综合数据库（GEO）数据集，确定远端同源盒 2（DLX2）在颅内动脉瘤中是一个显著上调的基因，并对其功能作用和上游机制进行了剖析。结果发现，DLX2 在颅内动脉瘤患者中表达升高。DLX2 沉默抑制了人主动脉血管平滑肌细胞（HA-VSMC）的增殖能力，并促进其凋亡。此外，DLX2 的缺失促进了胶原 I 和胶原 III 的产生，抑制了 MMP2/9 和促炎因子的水平。此外，组蛋白去甲基化酶 3（JMJD3）通过抑制 H3K27me3 修饰来促进 DLX2 的表达。JMJD3 耗竭在体外和体内具有与 DLX2 相同的功能，而在 JMJD3 敲低的情况下过表达 DLX2 会导致颅内动脉瘤的进展加剧，并增强 HA-VSMC 的存活。综上所述，JMJD3 通过抑制 H3K27me3 修饰来促进 DLX2 的表达，从而促进颅内动脉瘤的形成。
