Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow

Lingfang Zeng, Anna Zampetaki, Andriana Margariti, Anna Elena Pepe, Saydul Alam, Daniel Martin, Qingzhong Xiao, Wen Wang, Zheng-Gen Jin, Gillian Cockerill, Kazutoshi Mori, Yi-Shuan Julie Li, Yanhua Hu, Shu Chien, Qingbo Xu

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

X-box binding protein 1 (XBP1) is a key signal transducer in endoplasmic reticulum stress response, and its potential role in the atherosclerosis development is unknown. This study aims to explore the impact of XBP1 on maintaining endothelial integrity related to atherosclerosis and to delineate the underlying mechanism. We found that XBP1 was highly expressed at branch points and areas of atherosclerotic lesions in the arteries of ApoE(-/-) mice, which was related to the severity of lesion development. In vitro study using human umbilical vein endothelial cells (HUVECs) indicated that disturbed flow increased the activation of XBP1 expression and splicing. Overexpression of spliced XBP1 induced apoptosis of HUVECs and endothelial loss from blood vessels during ex vivo cultures because of caspase activation and down-regulation of VE-cadherin resulting from transcriptional suppression and matrix metalloproteinase-mediated degradation. Reconstitution of VE-cadherin by Ad-VEcad significantly increased Ad-XBP1s-infected HUVEC survival. Importantly, Ad-XBP1s gene transfer to the vessel wall of ApoE(-/-) mice resulted in development of atherosclerotic lesions after aorta isografting. These results indicate that XBP1 plays an important role in maintaining endothelial integrity and atherosclerosis development, which provides a potential therapeutic target to intervene in atherosclerosis.
Original languageEnglish
Pages (from-to)8326-31
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number20
DOIs
Publication statusPublished - 2009

Fingerprint Dive into the research topics of 'Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow'. Together they form a unique fingerprint.

  • Cite this

    Zeng, L., Zampetaki, A., Margariti, A., Pepe, A. E., Alam, S., Martin, D., Xiao, Q., Wang, W., Jin, Z-G., Cockerill, G., Mori, K., Li, Y-S. J., Hu, Y., Chien, S., & Xu, Q. (2009). Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proceedings of the National Academy of Sciences of the United States of America, 106(20), 8326-31. https://doi.org/10.1073/pnas.0903197106