| First Author | Sun Y | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 33 | Pages | 10401-6 |
| PubMed ID | 26243880 | Mgi Jnum | J:226558 |
| Mgi Id | MGI:5697758 | Doi | 10.1073/pnas.1504387112 |
| Citation | Sun Y, et al. (2015) Nuclear receptor RORalpha regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation. Proc Natl Acad Sci U S A 112(33):10401-6 |
| abstractText | Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor-related orphan receptor alpha (RORalpha) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that RORalpha expression was significantly increased and genetic deficiency of RORalpha substantially suppressed pathologic retinal neovascularization. Loss of RORalpha led to decreased levels of proinflammatory cytokines and increased levels of antiinflammatory cytokines in retinopathy. RORalpha directly suppressed the gene transcription of suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Inhibition of SOCS3 abolished the antiinflammatory and vasoprotective effects of RORalpha deficiency in vitro and in vivo. Moreover, treatment with a RORalpha inverse agonist SR1001 effectively protected against pathologic neovascularization in both oxygen-induced retinopathy and another angiogenic model of very-low-density lipoprotein receptor (Vldlr)-deficient (Vldlr (-/-) ) mice with spontaneous subretinal neovascularization, whereas a RORalpha agonist worsened oxygen-induced retinopathy. Our data demonstrate that RORalpha is a novel regulator of pathologic retinal neovascularization, and RORalpha inhibition may represent a new way to treat ocular neovascularization. |
