An allosteric peptide inhibitor of HIF-1α regulates hypoxia-induced retinal neovascularization

• DOI: 10.1073/pnas.2017234117
• Publication Date: 2020-10-27T00:42:27Z
• Authors: Ayumi Usui-Ouchi; Edith Aguilar; Salome Murinello; Mitchell Prins; Marin L. Gantner; Peter E. Wright; Rebecca B. Berlow; Martin Friedlander
• Keywords: 0301 basic medicine; Gene Expression; Retinal Neovascularization; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; Intrinsically Disordered Proteins; Mice, Inbred C57BL; Oxygen; Repressor Proteins; Mice; 03 medical and health sciences; HEK293 Cells; Trans-Activators; Animals; Humans; Protein Interaction Domains and Motifs; p300-CBP Transcription Factors; Hypoxia; Peptides; E1A-Associated p300 Protein

Significance Retinal ischemia causes hypoxia-induced neovascularization that stimulates production of proangiogenic cytokines such as VEGF by the hypoxia-inducible transcription factors HIF-1 and HIF-2. Current therapies for ischemic retinal diseases target circulating VEGF but do not modulate the activity of the transcription factors that control its production. We demonstrate that inhibiting HIF-mediated transcription with a peptide derived from the intrinsically disordered protein CITED2, a negative feedback regulator of HIF-1α, reduces pathological angiogenesis in a mouse model of ischemic retinopathy. Combining the CITED2 peptide with the VEGF-Trap aflibercept causes potent suppression of neovascularization and promotes revascularization of the ischemic retina, an outcome not observed for anti-VEGF agents alone, suggesting that dual targeting of the HIF transcription factors and VEGF may be advantageous.