May 2005
Volume 46, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2005
Geldanamycin Increases 4–Hydroxynonenal (HNE) –Induced Cytotoxic Effects in Human Retinal Pigment Epithelial Cells
Author Affiliations & Notes
  • M.J. Niittykoski
    Department of Ophthalmology,
    University of Kuopio, Kuopio, Finland
  • K. Kaarniranta
    Department of Ophthalmology,
    University of Kuopio, Kuopio, Finland
  • T. Ryhänen
    Department of Ophthalmology,
    University of Kuopio, Kuopio, Finland
  • E. Mannermaa
    Department of Pharmaceutics,
    University of Kuopio, Kuopio, Finland
  • T. Suuronen
    Department of Neuroscience and Neurology,
    University of Kuopio, Kuopio, Finland
  • A. Huhtala
    University of Tampere Medical School, Tampere, Finland
  • M. Teräsvirta
    Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
  • A. Salminen
    Department of Neuroscience and Neurology,
    University of Kuopio, Kuopio, Finland
  • H. Uusitalo
    Department of Ophthalmology,
    University of Kuopio, Kuopio, Finland
  • Footnotes
    Commercial Relationships  M.J. Niittykoski, None; K. Kaarniranta, None; T. Ryhänen, None; E. Mannermaa, None; T. Suuronen, None; A. Huhtala, None; M. Teräsvirta, None; A. Salminen, None; H. Uusitalo, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2005, Vol.46, 1621. doi:
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      M.J. Niittykoski, K. Kaarniranta, T. Ryhänen, E. Mannermaa, T. Suuronen, A. Huhtala, M. Teräsvirta, A. Salminen, H. Uusitalo; Geldanamycin Increases 4–Hydroxynonenal (HNE) –Induced Cytotoxic Effects in Human Retinal Pigment Epithelial Cells . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1621.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : Purpose: Development of age–related macular degeneration is associated with functional abnormalities and cell death in retinal pigment epithelial (RPE) cells attributable to oxidative stress. To minimize the adverse effects of oxidative stress, cells activate their defense systems, e.g. via increased expression of heat shock protein and activation of stress sensitive AP–1 and NF–kappaB transcription factors. We examined the accumulation of Hsp70 protein as well as activation of AP–1 and NF–kappaB transcription factors in human ARPE–19 cells subjected to a 4–hydroxynonenal (HNE) –induced oxidative stress. In addition, the influence of a specific Hsp90 inhibitor geldanamycin (GA) was studied in HNE–treated cells. Mitochondrial metabolic activity and caspase–3 activity were determined to evaluate cell death in the ARPE–19 cells. Methods: Hsp70 protein accumulation was analyzed by Western blotting and the DNA–binding activities of AP–1 and NF–kappaB were examined by gel mobility shift assay. MTT assay was used to determine cell viability by measuring their ability to metabolize 3–(4,5–dimethyldiazol–2–yl)–2,5–diphenyltetrazolium bromide. Caspase–3 enzyme activity was measured by assaying the cleavage of a fluorescent peptide substrate. Results: The ARPE–19 cells showed increased accumulation of Hsp70 protein while DNA–binding activities of AP–1 or NF–kappaB transcription factors were decreased in response to HNE. Interestingly, GA significantly increased cytotoxicity in the HNE–treated cells. No alterations in caspase–3 activity were observed. Conclusions: This study reveals that Hsp70 is highly expressed in response to HNE–induced oxidative stress. Furthermore, Hsp90 inhibition with GA leads to an increased cellular damage in the RPE cells. Thus, the heat shock proteins may play an important role in the cytoprotection of RPE cells subjected to oxidative stress.

Keywords: stress response • oxidation/oxidative or free radical damage • retinal pigment epithelium 
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