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

Feng Ming Ho, Wan-Wan Lin, Bing Chang Chen, Chien M. Chao, Chia Ron Yang, Lian Y. Lin, Chih Chang Lai, Shing H. Liu, Chiau S. Liau

Research output: Contribution to journalArticle

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Abstract

Our previous studies demonstrated that high glucose-induced apoptosis in human umbilical vein endothelial cells (HUVECs) is mediated by sequential activation of c-Jun N-terminal kinase (JNK) and caspase, and prevented by exogenous nitric oxide (NO). In this study we further elucidated the roles of the transcriptional factor NF-κB, phosphatidylinositol 3′-kinase (PI3K), Akt and endothelial nitric oxide synthase (eNOS) in the apoptosis of HUVECs induced by high glucose. The results showed that high glucose-induced apoptosis was significantly enhanced by PI3K inhibitors (wortmannin and LY294002), NOS inhibitor (NG-nitro-arginine methyl ester) and eNOS antisense oligonucleotide. In contrast, apoptosis was markedly reduced by NF-κB inhibitor (pyrrolidine dithiocarbamate, PDTC), NF-κB antisense oligonucleotide, NO donor (sodium nitroprusside, SNP), and overexpression of Akt. The high glucose-induced NF-κB activation and transient Akt phosphorylation were prevented by the presence of vitamin C. Moreover, high glucose-induced increase in eNOS expression was attenuated by PI3K inhibitors and the negative mutant of PI3K. The activity of JNK induced by high glucose was suppressed by NF-κB-specific antisense oligonucleotide. Taken together our results demonstrated that high glucose-induced HUVECs apoptosis is through NF-κB-dependent JNK activation and reactive oxygen species (ROS)-dependent Akt dephosphorylation. Activation of the ROS/PI3K/Akt/eNOS signaling pathway in early phase exerts protective effects against the induction of apoptosis by high glucose.

Original languageEnglish
Pages (from-to)391-399
Number of pages9
JournalCellular Signalling
Volume18
Issue number3
DOIs
Publication statusPublished - Mar 2006

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Phosphatidylinositol 3-Kinase
JNK Mitogen-Activated Protein Kinases
Nitric Oxide Synthase Type III
Endothelial Cells
Apoptosis
Glucose
Antisense Oligonucleotides
Human Umbilical Vein Endothelial Cells
Reactive Oxygen Species
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Nitric Oxide Donors
Nitroprusside
Caspases
Ascorbic Acid
Nitric Oxide
Phosphorylation

Keywords

  • Akt
  • Apoptosis
  • Endothelial cell
  • eNOS
  • High glucose
  • JNK
  • NF-κB
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cell Biology

Cite this

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 M.; Yang, Chia Ron; Lin, Lian Y.; Lai, Chih Chang; Liu, Shing H.; Liau, Chiau S.

In: Cellular Signalling, Vol. 18, No. 3, 03.2006, p. 391-399.

Research output: Contribution to journalArticle

Ho, Feng Ming ; Lin, Wan-Wan ; Chen, Bing Chang ; Chao, Chien M. ; Yang, Chia Ron ; Lin, Lian Y. ; Lai, Chih Chang ; Liu, Shing H. ; Liau, Chiau S. / 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. In: Cellular Signalling. 2006 ; Vol. 18, No. 3. pp. 391-399.
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abstract = "Our previous studies demonstrated that high glucose-induced apoptosis in human umbilical vein endothelial cells (HUVECs) is mediated by sequential activation of c-Jun N-terminal kinase (JNK) and caspase, and prevented by exogenous nitric oxide (NO). In this study we further elucidated the roles of the transcriptional factor NF-κB, phosphatidylinositol 3′-kinase (PI3K), Akt and endothelial nitric oxide synthase (eNOS) in the apoptosis of HUVECs induced by high glucose. The results showed that high glucose-induced apoptosis was significantly enhanced by PI3K inhibitors (wortmannin and LY294002), NOS inhibitor (NG-nitro-arginine methyl ester) and eNOS antisense oligonucleotide. In contrast, apoptosis was markedly reduced by NF-κB inhibitor (pyrrolidine dithiocarbamate, PDTC), NF-κB antisense oligonucleotide, NO donor (sodium nitroprusside, SNP), and overexpression of Akt. The high glucose-induced NF-κB activation and transient Akt phosphorylation were prevented by the presence of vitamin C. Moreover, high glucose-induced increase in eNOS expression was attenuated by PI3K inhibitors and the negative mutant of PI3K. The activity of JNK induced by high glucose was suppressed by NF-κB-specific antisense oligonucleotide. Taken together our results demonstrated that high glucose-induced HUVECs apoptosis is through NF-κB-dependent JNK activation and reactive oxygen species (ROS)-dependent Akt dephosphorylation. Activation of the ROS/PI3K/Akt/eNOS signaling pathway in early phase exerts protective effects against the induction of apoptosis by high glucose.",
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T1 - 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

AU - Ho, Feng Ming

AU - Lin, Wan-Wan

AU - Chen, Bing Chang

AU - Chao, Chien M.

AU - Yang, Chia Ron

AU - Lin, Lian Y.

AU - Lai, Chih Chang

AU - Liu, Shing H.

AU - Liau, Chiau S.

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N2 - Our previous studies demonstrated that high glucose-induced apoptosis in human umbilical vein endothelial cells (HUVECs) is mediated by sequential activation of c-Jun N-terminal kinase (JNK) and caspase, and prevented by exogenous nitric oxide (NO). In this study we further elucidated the roles of the transcriptional factor NF-κB, phosphatidylinositol 3′-kinase (PI3K), Akt and endothelial nitric oxide synthase (eNOS) in the apoptosis of HUVECs induced by high glucose. The results showed that high glucose-induced apoptosis was significantly enhanced by PI3K inhibitors (wortmannin and LY294002), NOS inhibitor (NG-nitro-arginine methyl ester) and eNOS antisense oligonucleotide. In contrast, apoptosis was markedly reduced by NF-κB inhibitor (pyrrolidine dithiocarbamate, PDTC), NF-κB antisense oligonucleotide, NO donor (sodium nitroprusside, SNP), and overexpression of Akt. The high glucose-induced NF-κB activation and transient Akt phosphorylation were prevented by the presence of vitamin C. Moreover, high glucose-induced increase in eNOS expression was attenuated by PI3K inhibitors and the negative mutant of PI3K. The activity of JNK induced by high glucose was suppressed by NF-κB-specific antisense oligonucleotide. Taken together our results demonstrated that high glucose-induced HUVECs apoptosis is through NF-κB-dependent JNK activation and reactive oxygen species (ROS)-dependent Akt dephosphorylation. Activation of the ROS/PI3K/Akt/eNOS signaling pathway in early phase exerts protective effects against the induction of apoptosis by high glucose.

AB - Our previous studies demonstrated that high glucose-induced apoptosis in human umbilical vein endothelial cells (HUVECs) is mediated by sequential activation of c-Jun N-terminal kinase (JNK) and caspase, and prevented by exogenous nitric oxide (NO). In this study we further elucidated the roles of the transcriptional factor NF-κB, phosphatidylinositol 3′-kinase (PI3K), Akt and endothelial nitric oxide synthase (eNOS) in the apoptosis of HUVECs induced by high glucose. The results showed that high glucose-induced apoptosis was significantly enhanced by PI3K inhibitors (wortmannin and LY294002), NOS inhibitor (NG-nitro-arginine methyl ester) and eNOS antisense oligonucleotide. In contrast, apoptosis was markedly reduced by NF-κB inhibitor (pyrrolidine dithiocarbamate, PDTC), NF-κB antisense oligonucleotide, NO donor (sodium nitroprusside, SNP), and overexpression of Akt. The high glucose-induced NF-κB activation and transient Akt phosphorylation were prevented by the presence of vitamin C. Moreover, high glucose-induced increase in eNOS expression was attenuated by PI3K inhibitors and the negative mutant of PI3K. The activity of JNK induced by high glucose was suppressed by NF-κB-specific antisense oligonucleotide. Taken together our results demonstrated that high glucose-induced HUVECs apoptosis is through NF-κB-dependent JNK activation and reactive oxygen species (ROS)-dependent Akt dephosphorylation. Activation of the ROS/PI3K/Akt/eNOS signaling pathway in early phase exerts protective effects against the induction of apoptosis by high glucose.

KW - Akt

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KW - JNK

KW - NF-κB

KW - Reactive oxygen species

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