title: Diacylglycerol kinase (DGK) inhibitor II (R59949) could suppress retinal neovascularization and protect retinal astrocytes in an oxygen-induced retinopathy model.
abstract: Hypoxia-inducible factors (HIF) play a fundamental role in retinal neovascularization (NV) induced by low oxygen tension. In the presence of oxygen, the HIF-α subunit becomes hydroxylated at specific prolyl residues by prolyl hydroxylases (PHD), which triggers HIF-α for degradation. In our present study, we examined the effect of R59949, the diacylglycerol kinase (DGK) inhibitor II, on the retinal NV and its potential mechanism in an oxygen-induced retinopathy (OIR) model. OIR model was induced by exposure of hyperoxia (75 % oxygen) to C57BL/6J mice from postnatal day 7 (P7) to P12 and then returned to room air. By intraperitoneal injection once a day (10 μg/g/day) from P12 to P17, R59949 not only effectively prevented pathologic NV but also preserved the astrocyte morphology. Furthermore, the expression of PHD-2 was upregulated and HIF-1α and vascular endothelial growth factor (VEGF) were downregulated in the retina of OIR mice following R59949 treatment. These findings suggested a potential possibility that R59949 suppressed retinal neovascular pathophysiology via PHD2/HIF-1α/VEGF pathway.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Boyu
authors.initials: B
authors.lastname: Yang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Yu
authors.forename: Huanjiao
authors.initials: H
authors.lastname: Zhou
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.forename: Fan
authors.initials: F
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Huang
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use*; D012160:Retina / Q000187:drug effects / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010880:Piperidines; D052999:Quinazolinones; D042461:Vascular Endothelial Growth Factor A; C058544:R 59949; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D019852:Diacylglycerol Kinase