Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow.
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.
Cardiovascular Division, King's College London BHF Centre, London, United Kingdom.
Lingfang
L
Zeng
Anna
A
Zampetaki
Andriana
A
Margariti
Anna Elena
AE
Pepe
Saydul
S
Alam
Daniel
D
Martin
Qingzhong
Q
Xiao
Wen
W
Wang
Zheng-Gen
ZG
Jin
Gillian
G
Cockerill
Kazutoshi
K
Mori
Yi-Shuan Julie
YS
Li
Yanhua
Y
Hu
Shu
S
Chien
Qingbo
Q
Xu
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis; D001158:Arteries / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042783:Endothelial Cells / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019154:Protein Splicing; D012039:Regional Blood Flow; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse