High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-κB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway

Ho, Feng Ming; Lin, Wan-Wan; Chen, Bing Chang; Chao, Chien Ming; Yang, Congrong; Lin, Lian Yu; Lai, Chih Chang; Liu, Shing‐Hwa; Liau, Chiau Suong

doi:10.1016/j.cellsig.2005.05.009

Cited by 220 publications

(171 citation statements)

References 34 publications

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“…It was recently demonstrated that saturated NEFAs are able to activate NFB in several cell systems, such as murine and human skeletal muscle cells (14,21), bovine eye pericytes (22), bovine aortic endothelial cells (16), and HUVECs (23). Since NFB activation by various physiological stimuli, e.g., IL-18 (24), high glucose (25), hypoxia (26), and TNF-␣ (27), is reported to trigger apoptosis in endothelial cells, the mechanism of lipoapoptosis described in this study appears plausible. Consistent with the antiapoptotic effect of unsaturated NEFAs observed in this study, unsaturated NEFAs are reported to inhibit NFB activation in endothelial cells (28) and macrophages (29) and to prevent saturated NEFA-induced apoptosis in rat insulinoma and human islet cells (30).…”

Section: Diabetes Vol 55 November 2006mentioning

confidence: 91%

Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-κB Activation

Staiger

Staiger²,

Weigert³

et al. 2006

Diabetes

128

107

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High nonesterified fatty acid (NEFA) concentrations, as observed in the metabolic syndrome, trigger apoptosis of human umbilical vein endothelial cells. Since endothelial apoptosis may contribute to atherothrombosis, we studied the apoptotic susceptibility of human coronary artery endothelial cells (HCAECs) toward selected NEFAs and the underlying mechanisms. HCAECs were treated with single or combined NEFAs. Apoptosis was quantified by flow cytometry, nuclear factor B (NFB) activation by electrophoretic mobility shift assay, and secreted cytokines by enzyme-linked immunosorbent assay. Treatment of HCAECs with saturated NEFAs (palmitate and stearate) increased apoptosis up to fivefold (P < 0.05; n ‫؍‬ 4). Unsaturated NEFAs (palmitoleate, oleate, and linoleate) did not promote apoptosis but prevented stearate-induced apoptosis (P < 0.05; n ‫؍‬ 4). Saturated NEFA-induced apoptosis neither depended on ceramide formation nor on oxidative NEFA catabolism. However, NEFA activation via acyl-CoA formation was essential. Stearate activated NFB and linoleate impaired stearate-induced NFB activation. Pharmacological inhibition of NFB and inhibitor of B kinase (IKK) also blocked stearate-induced apoptosis. Finally, the saturated NEFA effect on NFB was not attributable to NEFA-induced cytokine production. In conclusion, NEFAs display differential effects on HCAEC survival; saturated NEFAs (palmitate and stearate) are proapoptotic, and unsaturated NEFAs (palmitoleate, oleate, and linoleate) are antilipoapoptotic. Mechanistically, promotion of HCAEC apoptosis by saturated NEFA requires acyl-CoA formation, IKK, and NFB activation.

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Section: Diabetes Vol 55 November 2006mentioning

confidence: 91%

Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-κB Activation

Staiger

Staiger²,

Weigert³

et al. 2006

Diabetes

128

107

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“…It has been shown that ROS may play a key role in high glucose-induced apoptosis of mature vascular endothelial cells, which could be reversed by either eNOS activation or antioxidants (37,38). It was also suggested that hyperglycemia alone, through the mitochondrial (39 -41) and/or NAD(P)H oxidase-mediated (42) overproduction of ROS, can induce changes in gene expression and the behavior of vascular endothelial cells in diabetes.…”

Section: Discussionmentioning

confidence: 99%

High Glucose Impairs Early and Late Endothelial Progenitor Cells by Modifying Nitric Oxide–Related but Not Oxidative Stress–Mediated Mechanisms

et al. 2007

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OBJECTIVE-Endothelial progenitor cells (EPCs) are impaired in diabetes. This study aimed to investigate the direct effects of high glucose on EPCs.RESEARCH DESIGN AND METHODS-Mononuclear cells isolated from healthy subjects were incubated with glucose/ mannitol or drugs for EPC study. After 4 days of culture, attached early EPCs appeared. The monolayer late EPCs with cobblestone shape appeared at 2-4 weeks. Various immunofluroscence stainings were used to characterize the early and late EPCs. Senescence assay and the activity of endothelial nitric oxide synthase (eNOS) were determined. Migration and tube formation assay were done to evaluate the capacity for vasculogenesis in late EPCs.RESULTS-Chronic incubation with high glucose but not mannitol (osmotic control) dose-dependently reduced the number and proliferation of early and late EPCs, respectively. High glucose enhanced EPC senescence and impaired the migration and tube formation of late EPCs. High glucose also decreased eNOS, FoxO1, and Akt phosphorylation and bioavailable nitric oxide (NO) in both EPCs. The effects of high glucose could be ameliorated by coincubation with NO donor sodium nitroprusside or p38 mitogen-activated protein kinase inhibitor and deteriorated by eNOS inhibitor or PI3K (phosphatidylinositol 3Ј-kinase) inhibitor. Antioxidants including vitamin C, N-acetylcysteine-and polyethylene glycol (PEG)-conjugated superoxide dismutase, and PEG-catalase had no effects, whereas pyrrolidine dithiocarbamate, diphenyleneiodonium, apocynin, and rotenone even deteriorated the downregulation of both EPCs. CONCLUSIONS-High

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“…Under certain pathological conditions, HG treatment induced a biphasic response in cell growth, i.e. an early cell proliferation and a late cell apoptosis (Pascal et al 1996, Ho et al 2006. In order to understand the mechanism of biphasic response of EPC proliferation to HG, we investigated the effect of HG on cell cycle distribution.…”

Section: Discussionmentioning

confidence: 99%

Biphasic response of endothelial progenitor cell proliferation induced by high glucose and its relationship with reactive oxygen species

Zhang

Wang

Chen

et al. 2008

Journal of Endocrinology

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In this study, the effect of high glucose (HG) on endothelial progenitor cell (EPC) proliferation and its relationship with cyclins and reactive oxygen species (ROS) were investigated. Mouse EPCs were isolated from bone marrow using a magnetic activated cell-sorting system and cultured in the presence or absence of HG (30 mmol/l). We found that in the early stage of incubation (3 days), HG promoted cell proliferation, and increased the expressions of cdk2 and cyclin E, while in the late stage of culture (7 days) it inhibited cell proliferation and decreased the expressions of cdk2, cyclin E, and proliferating cell nuclear antigen (PCNA). Moreover, on the third day after incubation, HG significantly inhibited the apoptosis of EPCs, while in the late stage it markedly activated caspase-3 and promoted apoptosis. ROS generation in cells and maleic dialdehyde level in medium were significantly increased in HG group on the seventh day, whereas the expressions of superoxide dismutase and glutathione levels decreased. Tempol, a membrane-permeable radical scavenger, significantly inhibited ROS production in EPCs and partially reversed the HG-mediated inhibition of EPCs proliferation on the seventh day. We hypothesize that in the HG environment, the biphasic response of EPC proliferation may be related to the generation of ROS, which causes modulation of cyclins and cell cycle effect.

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High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-κB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway

Cited by 220 publications

References 34 publications

Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-κB Activation

Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-κB Activation

High Glucose Impairs Early and Late Endothelial Progenitor Cells by Modifying Nitric Oxide–Related but Not Oxidative Stress–Mediated Mechanisms

Biphasic response of endothelial progenitor cell proliferation induced by high glucose and its relationship with reactive oxygen species

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