基因敲除
势垒函数
紧密连接
细胞生物学
内皮干细胞
下调和上调
粘合连接
ALDH2
生物
调节器
化学
细胞
醛脱氢酶
基因
生物化学
钙粘蛋白
体外
作者
Kehui Yang,Sumei Cui,Jingwen Wang,Feng Xu,Hong Du,Hongwei Yue,Huaqing Ye,Jialin Guo,Jian Zhang,Pengpai Li,Yunyun Guo,Chang Pan,Jiaojiao Pang,Jiali Wang,Xiao Yu,Cheng Zhang,Zhiping Liu,Yuguo Chen,Feng Xu
标识
DOI:10.1002/advs.202302231
摘要
Abstract 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.
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