title: 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.
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.
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, 110-744, Republic of Korea.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Jo
authors.forename: Hongchan
authors.initials: H
authors.lastname: An
authors.forename: Dong-Jo
authors.initials: DJ
authors.lastname: Chang
authors.forename: Yi-Yong
authors.initials: YY
authors.lastname: Baek
authors.forename: Chang Sik
authors.initials: CS
authors.lastname: Cho
authors.forename: Hyoung Oh
authors.initials: HO
authors.lastname: Jun
authors.forename: So-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001253:Astrocytes; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D042783:Endothelial Cells; D015870:Gene Expression / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C578797:(S)-2-(3,4-dimethoxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)propan-1-one; C578796:2-(3,4-dimethoxyphenyl)-1-(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanone; D001578:Benzopyrans; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit