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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
- Source :
- Journal of molecular medicine (Berlin, Germany). 92(10)
- Publication Year :
- 2013
-
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.
- Subjects :
- Male
medicine.medical_treatment
Gene Expression
Retinal Neovascularization
Cell Line
Diabetes Mellitus, Experimental
Capillary Permeability
Downregulation and upregulation
Heat shock protein
Drug Discovery
medicine
Animals
Humans
Benzopyrans
HSP90 Heat-Shock Proteins
Hypoxia
Genetics (clinical)
Cells, Cultured
Retina
Diabetic Retinopathy
biology
Chemistry
Growth factor
Endothelial Cells
Diabetic retinopathy
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
Hsp90
Mice, Inbred C57BL
Vascular endothelial growth factor A
medicine.anatomical_structure
Astrocytes
Cancer research
biology.protein
Molecular Medicine
Retinopathy
Subjects
Details
- ISSN :
- 14321440
- Volume :
- 92
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Journal of molecular medicine (Berlin, Germany)
- Accession number :
- edsair.doi.dedup.....1f0ec5fd82633315c170898e095fb8f8