Unspliced X-box-binding Protein 1 (XBP1) Protects Endothelial Cells from Oxidative Stress through Interaction with Histone Deacetylase 3

Martin, Daniel; Li, Yang; Yang, Junyao; Wang, Gang; Margariti, Andriana; Jiang, Zhixin; Yu, Hui; Zampetaki, Anna; Hu, Yanhua; Xu, Qingbo; Zeng, Lingfang

doi:10.1074/jbc.m114.571984

Cited by 77 publications

(66 citation statements)

References 49 publications

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“…Taken together, these data suggest that the activation of the Nrf2-ARE pathway alone is not sufficient to induce endothelial MT-1 expression. It was recently reported that Nrf2 directly interacts with histone acetyltransferases (e.g., p300), histone deacetylases (HDACs), and chromatin remodeling factors (e.g., brahma regulated gene 1) (Sun et al, 2009;Martin et al, 2014;Zhang et al, 2006). Nrf2 may form a multiple complex with other proteins.…”

Section: Discussionmentioning

confidence: 99%

Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells

et al. 2016

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-Metallothionein (MT) plays a central role in cellular defense against heavy metals and oxidative stress. Since the induction of MT requires the activation of metal response element (MRE)-binding transcription factor-1 (MTF-1) by binding of zinc ions, inorganic zinc is regarded as a typical MT inducer. However, in a previous report, we showed that inorganic zinc could not induce MT in vascular endothelial cells. While it is suggested that endothelial MT presents mechanisms different from those of other cell types, these remain unclear. In this study, we investigated whether the induction of endothelial MT expression involves the Nrf2-ARE pathway using copper(II) bis(diethyldithiocarbamate), termed Cu10, using a culture system of bovine aortic endothelial cells. Cu10 induced MT-1/2 protein expression and increased the expression of mRNAs for MT-1A, MT-1E, and MT-2, MT isoforms expressed in the cells. Cu10 activated not only the MTF-1-MRE, but also the Nrf2-ARE pathway. MTF-1 knockdown resulted in the repression of Cu10-induced MT-1 and -2 expression. Cu10-induced MT-1 expression was down-regulated by Nrf2 knockdown. However, MT-2 expression was not affected by Nrf2 knockdown. These results suggest that the expression of endothelial MT is up-regulated by the Nrf2-ARE pathway as well as by the MTF-1-MRE pathway. Moreover, MT-1 regulation mechanisms differ from that of MT-2. Specifically, the present data support the hypothesis that MT-1 participates in the biological defense system, while MT-2 mainly regulates intracellular zinc metabolism.

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Section: Discussionmentioning

confidence: 99%

Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells

et al. 2016

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“…A role for ER stress is suggested given the upregulation or activation of several effectors of the UPR, such as IRE-1a, ATF-6, and XBP-1, following disturbed blood flow in atherosusceptible regions, such as curved or branching points of the aorta (Civelek et al, 2009;Feaver et al, 2008;Zeng et al, 2009). Here, the UPR effector unspliced XBP-1 is initially protective and promotes EC survival by shielding the endothelium from oxidative stress injury (Martin et al, 2014). When disturbed flow persists, sustained ER stress leads to XBP-1 splicing and triggers a detrimental pro-apoptotic response (Zeng et al, 2009).…”

Section: Upr In Atherosclerosismentioning

confidence: 96%

ER Stress and Angiogenesis

2015

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Proper tissue vascularization is vital for cellular function as it delivers oxygen, nutrients, hormones, and immune cells and helps to clear cellular debris and metabolic waste products. Tissue angiogenesis occurs to satisfy energy requirements and cellular sensors of metabolic imbalance coordinate vessel growth. In this regard, the classical pathways of the unfolded protein response activated under conditions of ER stress have recently been described to generate angiomodulatory or angiostatic signals. This review elaborates on the link between angiogenesis and ER stress and discusses the implications for diseases characterized by altered vascular homeostasis, such as cancer, retinopathies, and atherosclerosis.

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“…53 However, while spliced XBP1 (XPB1s), which positively regulates UPR, contributes to EC apoptosis and atherosclerosis formation, the unspliced XBP1 (XBP1u) can induce the antioxidant response. 54 Interestingly, disturbed flow elevated expression of antioxidant genes in ECs in XBP1u-and HDAC3 (histone deacetylase 3)-dependent manner. Increased expression of XBP1u and HDAC3 in HUVECs has decreased with KDR (kinase insert domain receptor) or PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibition.…”

Section: Endothelial Cellsmentioning

confidence: 99%