Impacts of Hypoxia-Inducible Factor-1 Knockout in the Retinal Pigment Epithelium on Choroidal Neovascularization

Lin, Mingkai; Hu, Yang; Chen, Ying; Zhou, Kelu; Jin, Jianhua; Zhu, Meili; Le, Yun Zheng; Ge, Jian; Xing, Jian

doi:10.1167/iovs.11-8936

Cited by 53 publications

(37 citation statements)

References 44 publications

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“…Lin et al knocked out HIF-1α in the RPE using the cre/lox system and suggested that RPE-derived HIF-1α plays a critical role in CNV [32]. Kurihare et al demonstrated the off-target effects resulting from the specific knockout of the VEGF gene in adult mice.…”

Section: Discussionmentioning

confidence: 99%

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Sun¹,

Cai²,

Liu³

2017

Cell Physiol Biochem

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Background/Aims: The goal of this study was to detect the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human retinal pigmented epithelial (RPE) cells treated with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, under hypoxic and normoxic conditions and to explore the signaling mechanism involved in regulating the hypoxia-induced expression of HIF-1α and VEGF in RPE cells. Methods: D407 cells were cultured in normoxic or hypoxic conditions, with or without celecoxib or a PI3K inhibitor (LY294002). The anti-proliferative effect of celecoxib was assessed using the MTT assay. RT-PCR, Western blotting and ELISA were performed to detect the levels of PI3K, phosphorylated AKT (p-AKT), HIF-1α, VEGF and COX-2. Results: Celecoxib inhibited the proliferation of RPE cells in a dose-dependent manner. Celecoxib suppressed the expression of VEGF at both the mRNA and protein levels and decreased HIF-1α protein expression. HIF-1α activation was regulated by the PI3K/AKT pathway. The celecoxib-induced down-regulation of HIF-1α and VEGF required the suppression of the hypoxia-induced PI3K/AKT pathway. However, the down-regulation of COX-2 did not occur in cells treated with celecoxib. Conclusions: The antiangiogenic effects of celecoxib in RPE cells under hypoxic conditions resulted from the inhibition of HIF-1α and VEGF expression, which may be partly mediated by a COX-2-independent, PI3K/AKT-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Sun¹,

Cai²,

Liu³

2017

Cell Physiol Biochem

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“…However, an important role for expression of HIF-1 in RPE cells and CNV has been demonstrated. 26 It is also possible that other factors such as age, insulin-like growth factor 1, inflammatory cytokines, transforming growth factor b, 1,5-7 and adrenergic signaling contribute to VEGF expression in CNV. The results of our study with adrenergic blockade suggest adrenergic signaling is one of the specific contributors to alterations in the ocular angiogenic balance and CNV.…”

Section: Discussionmentioning

confidence: 99%

Ocular Safety of Intravitreal Propranolol and Its Efficacy in Attenuation of Choroidal Neovascularization

Nourinia

Kanavi

Kaharkaboudi

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Nourinia R, Rezaei Kanavi M, Kaharkaboudi A, et al. Ocular safety of intravitreal propranolol and its efficacy in attenuation of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2015;56:8228-8235. DOI:10.1167/iovs.15-17169 PURPOSE. Determine the safe dose of intravitreal propranolol (IVP), and evaluate its inhibitory effect on laser-induced choroidal neovascularization (CNV). METHODS.To determine the IVP safe dose, 32 rabbits were divided into 4 groups. Three of these groups received IVP (15 lL) corresponding to 15 lg (group B), 30 lg (group C), and 60 lg (group D). The control group (A) received 15 lL saline. Safety was assessed by ocular examination, electroretinography (ERG), routine histopathologic evaluation, immunohistochemistry for glial fibrillary acidic protein (GFAP), and real-time qPCR for GFAP, VEGF, thrombospondin 1 (TSP1), and pigment epithelium-derived factor (PEDF). A similar experiment was performed in 24 mice by using a 100-fold lower amount of propranolol (0.15, 0.3, and 0.6 lg in 2 lL) based on vitreous volume. For assessment of the angioinhibitory effects of IVP, CNV was induced in 42 mice via laser burns. Mice were divided into two groups: group 1 received the safe dose of IVP (0.3 lg in 2 lL) and group 2 received saline. Neovascularization area was quantified by intercellular adhesion molecule (ICAM)-2 immunostaining of choroidal-scleral flat mounts by using ImageJ software.RESULTS. According to clinical, ERG, and histopathologic findings, 30 lg IVP was chosen as the safe dose in rabbit eyes, comparable to 0.3 lg IVP in mouse eyes. As compared to the control eyes, the development of CNV was attenuated (4.8-fold) in mice receiving 0.3 lg IVP.CONCLUSIONS. Intravitreal propranolol injection up to the final dose of 30 lg in rabbits and 0.3 lg in mice was safe, and was effective in attenuation of CNV in mice.

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“…Our results show that curcumin suppress the activation of NF-κB in the RPE-choroid complexes with CNV, which is consistent with the results of previous reports. HIF-1α, the main reactor of hypoxia, can activate the transcription of various angiogenic genes including VEGF and ICAM-1, and plays a pivotal role in angiogenesis [81]. HIF-1α expression was detected in surgically excised human CNV membranes [82]–[83] and its level elevated in the eyes of laser induced CNV animal models (23, 18032914, 22915031) [23], [81]–[84].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

et al. 2012

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PurposeTo investigate the effects of curcumin on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms.MethodsC57BL/6N mice were pretreated with intraperitoneal injections of curcumin daily for 3 days prior to laser-induced CNV, and the drug treatments were continued until the end of the study. The CNV area was analyzed by fluorescein-labeled dextran angiography of retinal pigment epithelium (RPE)-choroid flat mounts on day 7 and 14, and CNV leakage was evaluated by fluorescein angiography (FA) on day 14 after laser photocoagulation. The infiltration of F4/80 positive macrophages and GR-1 positive granulocytes were evaluated by immunohistochemistry on RPE-choroid flat mounts on day 3. Their expression in RPE-choroid complex was quantified by real-time PCR (F4/80) and Western blotting (GR-1) on day 3. RPE-choroid levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 were examined by ELISA on day 3. Double immunostaining of F4/80 and VEGF was performed on cryo-sections of CNV lesions on day 3. The expression of nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)−1α in the RPE-choroid was determined by Western blotting.ResultsCurcumin-treated mice had significantly less CNV area (P<0.05) and CNV leakage (P<0.001) than vehicle-treated mice. Curcumin treatment led to significant inhibition of F4/80 positive macrophages (P<0.05) and GR-1 positive granulocytes infiltration (P<0.05). VEGF mainly expressed in F4/80 positive macrophages in laser injury sites, which was suppressed by curcumin treatment (P<0.01). Curcumin inhibited the RPE-choroid levels of TNF-α (P<0.05), MCP-1 (P<0.05) and ICAM-1 (P<0.05), and suppressed the activation of NF-κB in nuclear extracts (P<0.05) and the activation of HIF−1α (P<0.05).ConclusionCurcumin treatment led to the suppression of CNV development together with inflammatory and angiogenic processes including NF-κB and HIF−1α activation, the up-regulation of inflammatory and angiogenic cytokines, and infiltrating macrophages and granulocytes. This provides molecular and cellular evidence of the validity of curcumin supplementation as a therapeutic strategy for the suppression of age-related macular degeneration (AMD)-associated CNV.

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Impacts of Hypoxia-Inducible Factor-1 Knockout in the Retinal Pigment Epithelium on Choroidal Neovascularization

Cited by 53 publications

References 44 publications

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Ocular Safety of Intravitreal Propranolol and Its Efficacy in Attenuation of Choroidal Neovascularization

Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

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