期刊
STROKE
卷 53, 期 4, 页码 1263-1275出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.120.032691
关键词
endothelial cell; genomics; leukocyte; permeability; risk factor
资金
- Canadian Institutes of Health Research (CIHR)
- Canada research Chairs
- Fonds de la Recherche du Quebec en Sante (FRQS)
- CIHR Frederick Banting & Charles Best Canada Graduate Scholarship
- McGill Faculty of Science
- Quebec Cell, Tissue and Gene Therapy Network-TheCell (FRQS)
This study reveals that RNF213 may play a crucial role in maintaining cerebral endothelial cell integrity, and its disruption may contribute to the early pathological mechanism of Moyamoya disease. Additionally, the study further emphasizes the importance of blood-brain barrier integrity.
Background: Variants in the ring finger protein 213 (RNF213) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease. Methods: To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology. Results: In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines. Conclusions: Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据