Oxidized phospholipids in oxidized low-density lipoprotein down-regulate thrombomodulin transcription in vascular endothelial cells through a decrease in the binding of RARβ-RXRα heterodimers and Sp1 and Sp3 to their binding sequences in the TM promoter

Ishii, Hidemi; Tezuka, Tsuyoshi; Ishikawa, Hiroyuki; Takada, Kohei; Oida, Koji; Horie, Shuichi

doi:10.1182/blood-2002-08-2428

Cited by 43 publications

(30 citation statements)

References 52 publications

(52 reference statements)

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“…In particular when HAECs were incubated with fenofibrate in the presence of oxidized LDL the effect of the medication was reversed (Figure 1 and Figure 4). While it is impossible to replicate the atheromatous environment in vitro, both TNF-α and oxidized LDL have been demonstrated within atherosclerosis and shown to modulate TM expression, supporting the relevance of these studies [31][32][33][34][35]. There are a number of other mechanisms which may account for the inter-sample variation in response to PPAR ligand incubation in this study.…”

Section: Discussionsupporting

confidence: 72%

Modulation of endothelial cell thrombomodulin by PPAR ligands — Variation according to environment

Mangan

Clancy

Golledge

2008

Thrombosis Research

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Section: Discussionsupporting

confidence: 72%

Modulation of endothelial cell thrombomodulin by PPAR ligands — Variation according to environment

Mangan

Clancy

Golledge

2008

Thrombosis Research

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“…Construction of Plasmids and Recombinant AdenovirusesThe TM reporter, pGL3TM1562 (Ϫ1562 to ϩ140), was constructed as described previously (27,28). The fragment from Ϫ1370 to 958 was removed by SmaI, yielding pGL3TM1562 (deletion 1370 -958).…”

Section: Methodsmentioning

confidence: 99%

Thrombomodulin Is a Clock-controlled Gene in Vascular Endothelial Cells

Takeda

Maemura

Horie

et al. 2007

Journal of Biological Chemistry

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106

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Cardiovascular diseases are closely related to circadian rhythm, which is under the control of an internal biological clock mechanism. Although a biological clock exists not only in the hypothalamus but also in each peripheral tissue, the biological relevance of the peripheral clock remains to be elucidated. In this study we searched for clock-controlled genes in vascular endothelial cells using microarray technology. The expression of a total of 229 genes was up-regulated by CLOCK/BMAL2. Among the genes that we identified, we examined the thrombomodulin (TM) gene further, because TM is an integral membrane glycoprotein that is expressed primarily in vascular endothelial cells and plays a major role in the regulation of intravascular coagulation. TM mRNA and protein expression showed a clear circadian oscillation in the mouse lung and heart. Reporter analyses, gel shift assays, and chromatin immunoprecipitation analyses using the TM promoter revealed that a heterodimer of CLOCK and BMAL2 binds directly to the E-box of the TM promoter, resulting in TM promoter transactivation. Indeed, the oscillation of TM gene expression was abolished in clock mutant mice, suggesting that TM expression is regulated by the clock gene in vivo. Finally, the phase of circadian oscillation of TM mRNA expression was altered by temporal feeding restriction, suggesting TM gene expression is regulated by the peripheral clock system. In conclusion, these data suggest that the peripheral clock in vascular endothelial cells regulates TM gene expression and that the oscillation of TM expression may contribute to the circadian variation of cardiovascular events.

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“…MM-LDL was shown to regulate all of these activities to promote a procoagulant state. 2,28,[39][40][41][42] The signal transduction pathway regulating the induction of TF mRNA levels by Ox-PAPC in HUVEC was shown to be mediated through both a PKC/Erk/EGR-1 pathway and a Ca++/calcineurin/NFAT pathway. 39 Both transcription factors, EGR-1 and NFAT, act together in regulating the TF promoter.…”

Section: Procoagulant Activitymentioning

confidence: 99%

Endothelial cell regulation by phospholipid oxidation products

Berliner

Gharavi

2008

Free Radical Biology and Medicine

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Oxidized phospholipids accumulate in atherosclerotic lesions, on lipoproteins, in other states of chronic inflammation, on apoptotic cells, necrotic cells and cells exposed to oxidative stress. These lipids regulate the transcription of over 1000 gene, regulating many endothelial functions, by activating several different cell surface receptors and multiple signaling pathways. These lipids also have important effects not involving transcription that regulate cell junctions and leukocyte binding. Thus these lipids are potent regulators of endothelial cell function with broad effects comparable in extent but differing from those of cytokines.

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Oxidized phospholipids in oxidized low-density lipoprotein down-regulate thrombomodulin transcription in vascular endothelial cells through a decrease in the binding of RARβ-RXRα heterodimers and Sp1 and Sp3 to their binding sequences in the TM promoter

Cited by 43 publications

References 52 publications

Modulation of endothelial cell thrombomodulin by PPAR ligands — Variation according to environment

Modulation of endothelial cell thrombomodulin by PPAR ligands — Variation according to environment

Thrombomodulin Is a Clock-controlled Gene in Vascular Endothelial Cells

Endothelial cell regulation by phospholipid oxidation products

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