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Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1?.

ABSTRACT: Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)-1? -VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF-1? have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF-1? as a master regulator of angiogenesis in hypoxic condition, using ?-lapachone, would confer protection against hypoxia-induced retinopathy without affecting physiological vascular development in mice with oxygen-induced retinopathy (OIR), an animal model of ROP. The effects of ?-lapachone were examined after intraocular injection in mice with OIR. Intraocular administration of ?-lapachone resulted in significant reduction in hypoxia-induced retinal neovascularization without retinal toxicity or perturbation of developmental retinal angiogenesis. Our results demonstrate that HIF-1?-mediated VEGF expression in OIR is associated with pathological neovascularization, not physiological angiogenesis. Thus, strategies blocking HIF-1? in the developing eye in the pathological hypoxia could serve as a novel therapeutic target for ROP.

SUBMITTER: Park SW

PROVIDER: S-EPMC4119393 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1α.

Park Sung Wook SW Kim Jin Hyoung JH Kim Ko-Eun KE Jeong Moon Hee MH Park Hyunsung H Park Bongju B Suh Young-Ger YG Park Woo Jin WJ Kim Jeong Hun JH

Journal of cellular and molecular medicine 20140218 5

Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)-1α -VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF-1α have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF-1α as a master regulator of angiogenesis in hypoxic condition, using β-lapachone, would confer protection ...[more]

PMID: 24533641

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Project description:Retinopathy of prematurity (ROP), which is characterized by retinal neovascularization (RNV), is a major cause of neonatal blindness. The primary treatment for ROP is anti-vascular endothelial growth factor (VEGF) therapy, which is costly and can rapidly lead to desensitization. Celastrol, a bioactive compound extracted from Tripterygium wilfordii Hook F. ("Thunder of God Vine"), has been shown to exert anticancer and anti-inflammatory effects. However, whether celastrol has antiangiogenic activity and can suppress inflammation to inhibit ROP progression is unclear. This was investigated in the present study in vitro as well as in vivo using a mouse model of oxygen-induced retinopathy (OIR). Our results showed that celastrol treatment reduced neovascular and avascular areas in the retina and inhibited microglia activation and inflammation in OIR mice. Celastrol also inhibited proliferation, migration, and tube formation in cultured human retinal microvascular endothelial cells, and reversed the activation of the microRNA (miR)-17-5p/hypoxia-inducible factor (HIF)-1α/VEGF pathway in the retina of OIR mice. These results indicate that celastrol alleviates pathologic RNV in the retina by protecting neuroglia and suppressing inflammation via inhibition of miR-17-5p/HIF-1α/VEGF signaling, and thus has therapeutic potential for the prevention and treatment of ROP.Abbreviations: BSA, bovine serum albumin; COX2, cyclooxygenase 2; ECM, endothelial cell medium; FBS, fetal bovine serum; HDAC, histone deacetylase; HIF-1, hypoxia-inducible factor 1; HRMEC, human retinal microvascular endothelial cell; Hsp70, heat shock protein; IB4, isolectin B4; ICAM-1, intercellular adhesion molecule 1; IL-1β/6, interleukin 1 beta/6; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein 1; miRNA, microRNA; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; OIR, oxygen-induced retinopathy; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidylinositol-3-kinase; qRT-PCR, quantitative real-time PCR; RNV, retinal neovascularization; ROP, retinopathy of prematurity; RTCA, real-time cell analyzer; RVO, retinal vaso-obliteration; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.

Dataset Information

Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1?.

Publications

Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1α.

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