Role of 4-hydroxynonenal in epidermal growth factor receptor-mediated signaling in retinal pigment epithelial cells

Rit Vatsyayan, Pankaj Chaudhary, Abha Sharma, Rajendra Sharma, Poorna Chandra Rao Lelsani, Sanjay Awasthi, Yogesh C. Awasthi

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Lipid peroxidation (LPO) end-product 4-hydroxynonenal (4-HNE) has been implicated in the mechanism of retinopathy. Lately it has been shown that besides being cytotoxic, 4-HNE plays an important role in oxidative stress-induced signaling. In this study, we have investigated the effect of 4-HNE on epidermal growth factor receptor (EGFR)-mediated signaling, its potential functional consequences, and the regulatory role of the 4-HNE metabolizing isozymes, glutathione S-transferase A4-4 (GSTA4-4) on this signaling in retinal pigment epithelial (RPE) cells. Our results showed that consistent with its known toxicity at relatively higher concentrations, 4-HNE induced cell death in RPE. However, at lower concentrations (as low as 0.1 μM) 4-HNE triggered phosphorylation of EGFR and activation of its down stream signaling components ERK1/2 and Akt that are known to be involved in cell proliferation. These effects of 4-HNE on EGFR could be attenuated by the over expression of GSTA4-4 that reduces intracellular levels of 4-HNE. Our results also indicated that 4-HNE-induced activation of EGFR is a protective mechanism against oxidative stress because EGFR, MEK, and PI3K inhibitors potentiated the toxicity of 4-HNE and also inhibited wound healing in a RPE cell model. These studies suggest that as an initial response to oxidative stress, 4-HNE induces protective mechanism(s) in RPE cells through EGFR-mediated signaling.

Original languageEnglish
Pages (from-to)147-154
Number of pages8
JournalExperimental eye research
Volume92
Issue number2
DOIs
StatePublished - Feb 2011

Keywords

  • 4-hydroxy-2-nonenal
  • Epidermal growth factor
  • Epidermal growth factor receptor
  • Glutathione S-transferases
  • Oxidative stress
  • Retinal pigment epithelium cells

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