Endothelial NOS-dependent activation of c-Jun NH(2)- terminal kinase by oxidized low-density lipoprotein.

Academic Article

Abstract

  • Oxidized low-density lipoprotein (oxLDL) is known to activate a number of signal transduction pathways in endothelial cells. Among these are the c-Jun NH(2)-terminal kinase (JNK), also known as stress-activated protein kinase, and extracellular signal-regulated kinase (ERK). These mitogen-activated protein kinases (MAP kinase) determine cell survival in response to environmental stress. Interestingly, JNK signaling involves redox-sensitive mechanisms and is activated by reactive oxygen and nitrogen species derived from both NADPH oxidases, nitric oxide synthases (NOS), peroxides, and oxidized low-density lipoprotein (oxLDL). The role of endothelial NOS (eNOS) in the activation of JNK in response to oxLDL has not been examined. Herein, we show that on exposure of endothelial cells to oxLDL, both ERK and JNK are activated through independent signal transduction pathways. A key role of eNOS activation through a phosphatidylinositol-3-kinase-dependent mechanism leading to phosphorylation of eNOS is demonstrated for oxLDL-dependent activation of JNK. Moreover, we show that activation of ERK by oxLDL is critical in protection against the cytotoxicity of oxLDL.
  • Keywords

  • NASA Discipline Cell Biology, Non-NASA Center, Animals, Aorta, Thoracic, Cattle, Cells, Cultured, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Flavonoids, Humans, JNK Mitogen-Activated Protein Kinases, Lipoproteins, LDL, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, NADPH Oxidases, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type III, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt
  • Digital Object Identifier (doi)

    Author List

  • Go YM; Levonen AL; Moellering D; Ramachandran A; Patel RP; Jo H; Darley-Usmar VM
  • Start Page

  • H2705
  • End Page

  • H2713
  • Volume

  • 281
  • Issue

  • 6