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Hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retina is suppressed by HIF-1α destabilization by SH-1242 and SH-1280, novel hsp90 inhibitors

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Abstract

In diabetic retinopathy (DR), visual deterioration is related with retinal neovascularization and vascular hyperpermeability. Anti-vascular endothelial growth factor (VEGF) agents are currently utilized to suppress retinal neovascularization and macular edema (ME); however, there are still concerns on the widespread use of them because VEGF is a trophic factor for neuronal and endothelial cells in the retina. As an alternative treatment strategy for DR, it is logical to address hypoxia-related molecules to treat DR because the retina is in relative hypoxia as DR progresses. In this study, we demonstrate that destabilization of hypoxia-inducible factor-1α (HIF-1α) by SH-1242 and SH-1280, novel heat shock protein 90 (hsp90) inhibitors, leads to suppression of hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retina. In vitro experiments showed that these inhibitors inhibited hypoxia-induced upregulation of target genes of HIF-1α and further secretion of VEGF. Furthermore, these inhibitors effectively suppressed expression of target genes of HIF-1α including vegfa in the retina of oxygen-induced retinopathy (OIR) mice. Interestingly, despite hsp90 inhibition, these inhibitors do not induce definite toxicity at the level of gene expression, cellular viability, and histologic integrity. We suggest that SH-1242 and SH-1280 can be utilized in the treatment of DR, as an alternative treatment of direct VEGF inhibition.

Key message

  • SH-1242 and SH-1280 are novel hsp90 inhibitors similar to deguelin.

  • HIF-1α destabilization by hsp90 inhibition leads to anti-angiogenic effects.

  • Despite hsp90 inhibition, both inhibitors do not induce definite toxicity.

  • HIF-1α modulation can be a safer therapeutic option than direct VEGF inhibition.

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Acknowledgments

This work was supported by the National Research Foundation grant funded by the Korea government (MEST) (2012-0006019), the Bio-Signal Analysis Technology Inno-vation Program (2009-0090895), the Global Research Laboratory Program (2011-0021874), the Pioneer Research Program (2012-0009544) of NRF/MEST, and the Seoul National University Research Fund (800-20130338).

Conflict of interest

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, 110-744, Republic of Korea

    Dong Hyun Jo, Chang Sik Cho, Hyoung Oh Jun, Jin Hyoung Kim & Jeong Hun Kim

  2. Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea

    Dong Hyun Jo & Jeong Hun Kim

  3. College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea

    Hongchan An, Dong-Jo Chang, Ho-Young Lee, Kyu-Won Kim, Jeewoo Lee & Young-Ger Suh

  4. Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Kangwon-do, 200-701, Republic of Korea

    Yi-Yong Baek & Young-Myeong Kim

  5. School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea

    So-Jung Park & Hyun-Ju Park

  6. Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, 110-744, Republic of Korea

    Jeong Hun Kim

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  1. Dong Hyun Jo
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Correspondence to Young-Ger Suh or Jeong Hun Kim.

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Jo, D.H., An, H., Chang, DJ. et al. Hypoxia-mediated retinal neovascularization and vascular leakage in diabetic retina is suppressed by HIF-1α destabilization by SH-1242 and SH-1280, novel hsp90 inhibitors. J Mol Med 92, 1083–1092 (2014). https://doi.org/10.1007/s00109-014-1168-8

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  • DOI: https://doi.org/10.1007/s00109-014-1168-8

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