Induction of vascular endothelial growth factor by 4-hydroxynonenal and its prevention by glutathione precursors in retinal pigment epithelial cells

Eur J Pharmacol. 2002 Aug 9;449(3):213-20. doi: 10.1016/s0014-2999(02)02043-5.


Although 4-hydroxynonenal, a highly reactive lipid peroxidation product, is implicated in several age-related disorders such as Alzheimer's and Parkinson's diseases, its role in age-related macular degeneration is not known. The purpose of this study was to determine whether 4-hydroxynonenal increases vascular endothelial growth factor (VEGF) expression in human retinal pigment epithelial cells (ARPE-19), a source of VEGF in choroidal neovascularization observed in age-related macular degeneration. In addition, it was the purpose of this study to assess whether glutathione (GSH) and GSH precursors can inhibit the effects of 4-hydroxynonenal. At 1 micro M, 4-hydroxynonenal did not alter cell viability, but elevated VEGF secretion and mRNA expression by 35% (p<0.05) and 1.9-fold (p<0.05), respectively. However, at concentrations 5 microM and above, 4-hydroxynonenal reduced VEGF secretion as well as cell viability. At 1 and 10 microM, 4-hydroxynonenal did not induce apoptosis in ARPE-19 cells. 4-Hydroxynonenal (1 microM) reduced intracellular GSH by 25% (p<0.05) and increased oxidative stress by 50% (p<0.05). GSH precursor pretreatment for 1 h, which increased intracellular GSH levels by 50% (p<0.05), as well as GSH co-treatment, inhibited the VEGF-inductive and cytotoxic effects of 4-hydroxynonenal. Thus, 4-hydroxynonenal (1 microM) induces VEGF expression and secretion in ARPE-19 cells. This effect is likely due to GSH depletion and an associated increase in intracellular oxidative stress, resulting in increased VEGF mRNA levels. 4-Hydroxynonenal-mediated VEGF secretion as well as cytotoxicity can be reversed with GSH precursor pretreatment or GSH co-treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / pharmacology*
  • Apoptosis / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Endothelial Growth Factors* / biosynthesis*
  • Eye Proteins / metabolism
  • Glutathione / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins* / biosynthesis*
  • Lipid Peroxidation
  • Lymphokines* / biosynthesis*
  • Oxidative Stress / physiology
  • Pigment Epithelium of Eye / cytology
  • Pigment Epithelium of Eye / drug effects
  • Pigment Epithelium of Eye / metabolism*
  • RNA, Messenger / biosynthesis
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Aldehydes
  • Cysteine Proteinase Inhibitors
  • Endothelial Growth Factors
  • Eye Proteins
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Glutathione
  • 4-hydroxy-2-nonenal