Department of Emergency Medicine, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
Adv Sci (Weinh). 2023 Nov;10(32):e2302231. doi: 10.1002/advs.202302231. Epub 2023 Oct 11.
The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single-cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)-induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier-related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early-stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post-Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2-specific knockdown in ECs holds therapeutic potential in the early management of AAAs.
内皮屏障功能在腹主动脉瘤（AAA）及其上游调节因子中的作用尚不清楚。单细胞 RNA 测序显示，在血管紧张素 II（Ang II）诱导的 AAA 进展过程中，破坏内皮细胞焦点连接是一个早期（3 天）和持续（28 天）的事件。同样，对人主动脉夹层组织的 mRNA 测序证实，内皮屏障相关基因的表达下调。醛脱氢酶 2（ALDH2）是 AAA 的负调节因子，在 AAA 样本的内膜中被发现上调，导致测试其在早期 AAA 中的作用。ALDH2 在血管内皮细胞（EC）中的敲低/敲除特异性显著增加与焦点黏附及紧密连接相关的 EC 屏障标记物的表达，恢复内皮屏障完整性，并抑制 AAA 的早期主动脉扩张（Ang II 后 7 天和 14 天）。从机制上讲，ELK3 作为 ALDH2 下游的内皮屏障功能保护的调节因子。在分子水平上，ALDH2 直接与 LIN28B 结合，后者是 ELK3 mRNA 稳定性的调节剂，阻碍 LIN28B 与 ELK3 mRNA 的结合，从而抑制 ELK3 的表达并损害内皮屏障功能。因此，通过在 EC 中特异性敲低 ALDH2 来维持血管内皮屏障完整性，在 AAA 的早期治疗中具有潜在的治疗价值。
