Activation of JNK and Transcriptional Repressor ATF3/LRF1 through the IRE1/TRAF2 Pathway Is Implicated in Human Vascular Endothelial Cell Death by Homocysteine

Zhang, Chun; Kawauchi, Junya; Adachi, Mio; Hashimoto, Yoshinori; Oshiro, Satoru; Aso, Teijiro; Kitajima, Shigetaka

doi:10.1006/bbrc.2001.6044

Cited by 97 publications

(62 citation statements)

References 31 publications

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“…Multiple studies have shown the participation of JNK in endothelial cell death (33,49,52). p-JNK kinase expression was slightly induced by both modified LDLs.…”

Section: Discussionmentioning

confidence: 93%

Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway

Apostolov¹,

Basnakian²,

Yin³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Apostolov EO, Basnakian AG, Yin X, Ok E, Shah SV. Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway. Am J Physiol Heart Circ Physiol 292: H1836 -H1846, 2007. First published December 22, 2006; doi:10.1152/ajpheart.01079.2006.-The ability of modified low-density lipoptoteins (LDLs) to induce both proliferation and death of endothelial cells is considered to be a mechanism of early atherosclerosis development. We previously showed that carbamylated LDL (cLDL) induces human coronary artery endothelial cell (HCAEC) death in vitro. This effect is similar to the atherogenic action of oxidized LDL (oxLDL) that induces the proliferation and death of endothelial cells. The present study was designed to analyze a potential proliferative effect of cLDL and whether proliferation caused by modified LDLs is related to cell death. Cultured HCAECs were exposed to different concentrations of modified LDL or native LDL for varying periods of time. Cell proliferation measured by bromodeoxyuridine incorporation and S-phase analysis was dosedependently increased in the presence of cLDL (6.25-200 g/ml). The proliferation induced by cLDL or oxLDL was associated with cell death and increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2-terminal kinase (JNK). Inhibition of cLDL-or oxLDL-induced proliferation by aphidicolin (1 g/ml) was protective against both short-term cell death measured by lactate dehydrogenase release into the medium and long-term cell viability visualized by cell multiplication. Inhibition of ERK phosphorylation led to a significant decrease of DNA synthesis and cell rescue from injury by modified LDLs, while inhibition of JNK phosphorylation had an only partial rescue effect without involvement in cell proliferation. These data are the first evidence that endothelial cell death induced by cLDL or oxLDL is mediated by cell proliferation through the mitogen-activated protein kinase pathway. carbamylation; carbamylated low-density lipoprotein; oxidized lowdensity lipoprotein; mitogen-activated protein kinase; atherosclerosis CARBAMYLATION is a spontaneous, nonenzymatic reaction of protein modification by cyanate derived from urea, which is normally present in human plasma and is elevated in uremic patients (27). Chronic kidney disease in humans is associated with a several times increased risk of developing cardiovascular diseases because of accelerated atherosclerosis (12,32,47). The mechanism of uremia-induced atherosclerosis is not quite understood. We previously showed (2, 36, 37) that carbamylated low-density lipoprotein (cLDL) induces injury or dysfunction of endothelial cells and is present in human plasma in high quantities. Our recent observation (38) that cLDL induces cell death of human coronary artery endothelial cells (HCAECs) in vitro provided support for this hypothesis.It is commonly accepted that modified LDLs are important for early atherosclerosis initiation and progression (39, 43). Endothelial dysfunction i...

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“…Multiple studies have shown the participation of JNK in endothelial cell death (33,49,52). p-JNK kinase expression was slightly induced by both modified LDLs.…”

Section: Discussionmentioning

confidence: 93%

Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway

Apostolov¹,

Basnakian²,

Yin³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…26 -30 For example, ATF3 has been implicated in cytokine-induced or nitric oxide-induced ␤-cell apoptosis in the pancreas, 27 plays a role in homocysteine-induced endothelial cell death, 28 and promotes cancer cell death. 29,30 Regardless, because ATF3 is rapidly induced on I/R injury in the brain, 31 heart, 13 or liver, 14 in addition to the kidney, ATF3 may protect these organs against I/R-induced damage, such as ischemic stroke in the brain or acute myocardial infarction in the heart, which will be examined in future studies.…”

Section: Discussionmentioning

confidence: 99%

ATF3-Mediated Epigenetic Regulation Protects against Acute Kidney Injury

Cheng

Liao

et al. 2010

Journal of the American Society of Nephrology

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A variety of stress stimuli, including ischemia-reperfusion (I/R) injury, induce the transcriptional repressor ATF3 in the kidney. The functional consequences of this upregulation in ATF3 after renal I/R injury are not well understood. Here, we found that ATF3-deficient mice had higher renal I/R-induced mortality, kidney dysfunction, inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin), and apoptosis compared with wild-type mice. Furthermore, gene transfer of ATF3 to the kidney rescued the renal I/R-induced injuries in the ATF3-deficient mice. Molecular and biochemical analysis revealed that ATF3 interacted directly with histone deacetylase 1 (HDAC1) and recruited HDAC1 into the ATF/NF-B sites in the IL-6 and IL-12b gene promoters. The ATF3-associated HDAC1 deacetylated histones, which resulted in the condensation of chromatin structure, interference of NF-B binding, and inhibition of inflammatory gene transcription after I/R injury. Taken together, these data demonstrate epigenetic regulation mediated by the stress-inducible gene ATF3 after renal I/R injury and suggest potential targeted approaches for acute kidney injury.

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“…We have also searched promoters of the down-regulated genes, and of the 66 available promoters 5 (7.6%) contained a potential XBP1-binding motif, which is close to 6.4% found in whole genome, further supporting the significance of the overrepresentation of this motif in the promoters of the up-regulated genes. As Table I shows, one of those genes containing a potential XBP1-binding motif is ATF3, shown previously to be activated via the IRE1 pathway (40). ATF3 can be induced by many cellular signals, and although it has been shown to be important for liver regeneration (12,42), its specific role in the stress response is not understood.…”

Section: Time Course Of Nfb and Bip Activation In Transfected Hepg2mentioning

confidence: 99%

Gene Expression Changes Associated with the Endoplasmic Reticulum Stress Response Induced by Microsomal Cytochrome P450 Overproduction

Szczesna-Skorupa

Chen

Liu³

et al. 2004

Journal of Biological Chemistry

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Induction of drug-metabolizing microsomal cytochromes P450 (P450s) results in a striking proliferation of the smooth endoplasmic reticulum (ER). Overexpression of P450s in yeast and cultured cells produces a similar response. The signals mediating this process are not known but probably involve signal transduction pathways involved in the unfolded protein response (UPR) or the ER overload response (EOR). We have examined the temporal response of specific genes in these pathways and genes globally to overexpression of P450 in cultured cells. Activity of NFB, an EOR component, was substantially increased by overexpression of fulllength P450 2C2 or a chimera with the 28-amino acid signal anchor sequence of P450 2C2 in HepG2 cells, and the activation correlated temporally with the accumulation of P450 in the cells. In the UPR pathway, activation of the transcription factor XBP1 by IRE1 also correlated with the accumulation of P450 in the cells, and in contrast, maximum activation of the BiP/grp78 promoter preceded the accumulation. Differential effects of expression of P450 on apoptosis were observed in nonhepatic COS1 and hepatic HepG2 cells. In COS1 cells, apoptosis was induced, and this correlated with sustained activation of the pro-apoptotic JNK pathway, induction of CHOP, and an absence of the increased NFB activity. In HepG2 cells, JNK was only transiently activated, and CHOP expression was not induced. As assessed by DNA microarray analysis, up-regulation of signaling genes was predominant including those involved in anti-apoptosis and ER stress. These results suggest that both the EOR and UPR pathways are involved in the cellular response to induction of P450 expression and that in hepatic cells genes are also induced to block apoptosis, which may be a physiologically relevant response to prevent cell death during xenobiotic induced expression of P450 in the liver.

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Activation of JNK and Transcriptional Repressor ATF3/LRF1 through the IRE1/TRAF2 Pathway Is Implicated in Human Vascular Endothelial Cell Death by Homocysteine

Cited by 97 publications

References 31 publications

Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway

Modified LDLs induce proliferation-mediated death of human vascular endothelial cells through MAPK pathway

ATF3-Mediated Epigenetic Regulation Protects against Acute Kidney Injury

Gene Expression Changes Associated with the Endoplasmic Reticulum Stress Response Induced by Microsomal Cytochrome P450 Overproduction

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