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

Cell Signal. 2006 Mar;18(3):391-9. doi: 10.1016/j.cellsig.2005.05.009. Epub 2005 Jun 20.

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-kappaB, 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-kappaB inhibitor (pyrrolidine dithiocarbamate, PDTC), NF-kappaB antisense oligonucleotide, NO donor (sodium nitroprusside, SNP), and overexpression of Akt. The high glucose-induced NF-kappaB 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-kappaB-specific antisense oligonucleotide. Taken together our results demonstrated that high glucose-induced HUVECs apoptosis is through NF-kappaB-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Apoptosis*
  • Caspase 3
  • Caspases / genetics
  • Caspases / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Chromones / pharmacology
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology*
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glucose / pharmacology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / physiology*
  • Morpholines / pharmacology
  • Mutation
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Nitric Oxide / pharmacology
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / physiology*
  • Nitroarginine / pharmacology
  • Nitroprusside / pharmacology
  • Oligonucleotides, Antisense / pharmacology
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / physiology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Proline / analogs & derivatives
  • Proline / pharmacology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Thiocarbamates / pharmacology
  • Umbilical Veins / cytology
  • Wortmannin

Substances

  • Androstadienes
  • Chromones
  • Morpholines
  • NF-kappa B
  • Oligonucleotides, Antisense
  • Phosphoinositide-3 Kinase Inhibitors
  • Reactive Oxygen Species
  • Thiocarbamates
  • prolinedithiocarbamate
  • Nitroprusside
  • Nitroarginine
  • Nitric Oxide
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Proline
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Oncogene Protein v-akt
  • JNK Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • Glucose
  • Wortmannin