Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice

Zhou, Ji; Werstuck, Geoff H.; Lhoták, Šárka; Koning, A. B. Lawrence de; Sood, Sudesh K.; Hossain, Gazi S.; Møller, Jan; Ritskes‐Hoitinga, Merel; Falk, Erling; Dayal, Sanjana; Lentz, Steven R.; Austin, Richard C.

doi:10.1161/01.cir.0000134487.51510.97

Cited by 147 publications

(139 citation statements)

References 52 publications

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“…Furthermore, ER stress may underlie cell death following ischemia-reperfusion (52). In addition, damage to vascular cells by ER stress in hyperhomocysteinemic states promotes the development of atherosclerosis (53)(54)(55)(56). Thus, approaches that target HO-1 or CO to sites of ER stress offer a promising therapeutic modality in treating a variety of disorders related to ER stress.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Liu¹,

Peyton²,

Ensenat³

et al. 2005

Journal of Biological Chemistry

116

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Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO). In the present study, we found that endoplasmic reticulum (ER) stress induced by a variety of experimental agents stimulated a time-and concentration-dependent increase in HO-1 mRNA and protein in vascular smooth muscle cells (SMC). The induction of HO-1 by ER stress was blocked by actinomycin D or cycloheximide and was independent of any changes in HO-1 mRNA stability. Luciferase reporter assays indicated that ER stress stimulated HO-1 promoter activity via the antioxidant response element. Moreover, ER stress induced the nuclear import of Nrf2 and the binding of Nrf2 to the HO-1 antioxidant response element. Interestingly, ER stress stimulated SMC apoptosis, as demonstrated by annexin V binding, caspase-3 activation, and DNA laddering. The induction of apoptosis by ER stress was potentiated by HO inhibition, whereas it was prevented by addition of HO substrate. In addition, exposure of SMC to exogenously administered CO inhibited ER stress-mediated apoptosis, and this was associated with a decrease in the expression of the proapoptotic protein, GADD153. In contrast, the other HO-1 products failed to block apoptosis or GADD153 expression during ER stress. These results demonstrated that ER stress is an inducer of HO-1 gene expression in vascular SMC and that HO-1-derived CO acts in an autocrine fashion to inhibit SMC apoptosis. The capacity of ER stress to stimulate the HO-1/CO system provides a novel mechanism by which this organelle regulates cell survival.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Liu¹,

Peyton²,

Ensenat³

et al. 2005

Journal of Biological Chemistry

116

View full text Add to dashboard Cite

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“…Homocysteine-induced expression of MCP-1 and IL-8 has been shown to occur through activation of NF-kB, a transcription factor known to stimulate the production of cytokines, chemokines, leukocyte adhesion molecules, and hemopoetic growth factors -all of which are thought to contribute to vascular inflammation and atherogenesis. [1][2][3] The recent observations that NF-kB activation and downstream proinflammatory mediators and cytokines are increased in atherosclerotic lesions from hyperhomocysteinemic apolipoprotein E-deficient mice 28,62 further supports the concept that HHcy accelerates atherogenesis by causing vascular inflammation.…”

Section: Hhcy and Atherothrombosis: Potential Cellular Mechanisms Infmentioning

confidence: 91%

“…Our finding that ER stress and NF-kB activation are increased in the atherosclerotic lesions of mice with diet-induced HHcy provides support for this concept. 62 A recent study by Wang et al 27 has also shown that genetic hyperhomocysteimia in a hyperlipidemic background accelerates atherosclerosis. Using compound apoE and CBS double knockout mice, atherosclerotic lesion area and lipid content increased with total plasma homocysteine concentrations, independent of diet.…”

Section: Animal Models Of Hhcy-induced Atherogenesismentioning

confidence: 97%

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

2004

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Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine b-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic-and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

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“…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 XBP1 in vascular disease has not been examined in detail. In the present study, we demonstrated that disturbed flow induces XBP1 splicing and sustained activation that led to EC apoptosis and the formation of atherosclerotic lesion in ApoE Ϫ/Ϫ mice.…”

mentioning

confidence: 99%

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

Zeng

Zampetaki

Margariti

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

195

184

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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...

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Association of Multiple Cellular Stress Pathways With Accelerated Atherosclerosis in Hyperhomocysteinemic Apolipoprotein E-Deficient Mice

Cited by 147 publications

References 52 publications

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Endoplasmic Reticulum Stress Stimulates Heme Oxygenase-1 Gene Expression in Vascular Smooth Muscle

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

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

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