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

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 VEcadherin 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.caspase ͉ endothelial integrity ͉ Ve-cadherin ͉ vessel graft ͉ mouse model A therosclerosis is a leading cause of death worldwide (1, 2).Accumulating evidence suggests that atherosclerosis is a multifactorial disease that can be initiated by risk factors (3-6). An important feature of atherosclerosis is its geographic distribution along the artery wall, i.e., occurring more frequently at curved or branching points in the vasculature, indicating that the flow pattern exerts an important role in the development of atherosclerotic lesions (7,8).Endothelial cells (ECs) are key cellular components of blood vessels, functioning as selectively permeable barriers between blood and tissues. It is believed that risk factors induce EC apoptosis, leading to the denudation or dysfunction of the intact endothelial monolayer, which causes lipid accumulation, monocyte adhesion, and inflammatory reactions that initiate atherosclerotic lesion (5, 9-12). Although information on risk factorinduced atherosclerosis has been accumulating, the underlying mechanism remains unclear.The X-box binding protein 1 (XBP1) was originally identified as a bZIP protein capable of binding to the cis-acting X box present in the promoter regions of human major histocompatibility complex class II genes (13) and is known to be essential for liver growth and B lymphocyte differentiation (14,15). In mammalian cells, XBP1 is a key signal transducer in the endoplasmic reticulum (ER) stress response. It has also been reported that there is a link between XBP1 and human disease (16,17). Although ER stress is reported to be involved in atherosclerosis (18)(19)(20)(21)(22), the role of XB...

XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling

“…Our previous study has demonstrated that XBP1 splicing can contribute to EC apoptosis and atherosclerosis development. 30 However, in this study, we did not observe SMC apoptosis after XBP1s overexpression. The major role of XBP1 in SMC activation may be migration and proliferation.…”

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

“…First, a profound increase in IRE1 phosphorylation and XBP1s expression is observed in atherosclerotic plaques of mice and humans (8,10). Second, mechanical sheer stresses activate IRE1, whereas cardiovascular disease risk factors, such as oxidized phospholipids and homocysteine, induce both IRE1 and PERK (5,(25)(26)(27)(28)(29).…”

“…Work over the last decade has pinpointed ER stress as a driving force for atherosclerosis progression (5,(7)(8)(9)(10). For example, inhibiting the apoptotic signaling downstream of ER stress through genetic deletion of the proapoptotic transcription factor CCAAT box binding enhancer homologous protein (CHOP) or the signal transducer c-jun N-terminal kinase (JNK) blocks atherosclerosis progression (5,(11)(12)(13).…”

“…Second, mechanical sheer stresses activate IRE1, whereas cardiovascular disease risk factors, such as oxidized phospholipids and homocysteine, induce both IRE1 and PERK (5,(25)(26)(27)(28)(29). Third, experimentally sustained Xbp1 mRNA splicing in the vessel wall promotes atherosclerosis, whereas its ablation ameliorates hypercholesterolemia in obese or apolipoprotein E-deficient (ApoE −/− ) mice (10,30). Two small molecules, STF-083010 and 4μ8C, which selectively inhibit IRE1's RNase function, have been used in cells and animals to produce favorable therapeutic outcomes in other disease settings: STF-083010 reduced growth of multiple myeloma (21,24,31,32), and 4μ8c suppressed inflammation in a murine arthritis model (33).…”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…Among these pathways, autophagy (a process in which cells recycle their components to survive during starvation) and mitophagy [62] and the mitochondrial and endoplasmic reticulum unfolded protein response [63,64] (triggered in response to an accumulation of misfolded proteins in order to regulate protein homeostasis) could offer potential new therapeutic targets to mitigate ischemia-reperfusion injury (Table 2) [65][66][67][68][69][70][71]. Moreover, the uncontrolled unfolded protein response is pathological during ischemia, as has been observed in our in vitro models of ischemia-reperfusion.…”