Flt-1 Intraceptors Inhibit Hypoxia-Induced VEGF Expression In Vitro and Corneal Neovascularization In Vivo

Singh, Nirbhai; Amin, Shivan; Richter, Elizabeth R.; Rashid, Saadia; Scoglietti, Vincent C.; Jani, Pooja D.; Wang, Jin; Kaur, Rajwinder; Ambati, Jayakrishna; Dong, Zheng; Ambati, Balamurali K.

doi:10.1167/iovs.04-1172

Cited by 66 publications

(50 citation statements)

References 38 publications

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“…Cancer cells acquire genetic and adaptive changes allowing them to survive and proliferate in a hypoxic microenvironment. In the cornea, hypoxia leads to pathological conditions in the cornea, such as neovascularization, re-epithelialization attenuation, and apoptosis (1)(2)(3)(4)(5). Hypoxia-induced cellular responses include activation of signaling events and gene expression that control important cellular function affecting cell cycle progression and apoptosis.…”

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confidence: 99%

Activation of Polo-like Kinase 3 by Hypoxic Stresses

Wang

Gao

Dai

et al. 2008

Journal of Biological Chemistry

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Adequate oxygen supply is required for normal tissue function. Vascular deficiency and physical isolation from oxygen sources are the usual causes of oxygen deprivation in tissues (hypoxia). Hypoxic conditions develop in most solid tumors as a result of insufficient blood supply. Cancer cells acquire genetic and adaptive changes allowing them to survive and proliferate in a hypoxic microenvironment. In the cornea, hypoxia leads to pathological conditions in the cornea, such as neovascularization, re-epithelialization attenuation, and apoptosis (1-5). Hypoxia-induced cellular responses include activation of signaling events and gene expression that control important cellular function affecting cell cycle progression and apoptosis. Cellular responses to hypoxia are complex and dependent upon different levels of oxygen tension (6). Furthermore, these cellular responses determine hypoxia-affected organs. The signaling pathways underlying the cellular response to hypoxic stress most likely consist of sensors, signal transducers, and effectors (7). Although the hypoxic sensors have been identified (8, 9), the molecular entities responsible for transducing damage signals to specific effectors are just beginning to be revealed. Recent studies indicate that both ATM/ATR and Chk were activated in hypoxia-treated cells, suggesting that there may be DNA damage. Further downstream, hypoxia stimulates increased phosphorylation of p53, a major molecule executing DNA damage (10, 11). In addition, hypoxia-induced cellular responses resemble the effects of other stress stimuli, including UV irradiation, reactive oxygen species (ROS), 2 and osmotic shock (12, 13). For example, hypoxic stress activates MAP kinases including c-Jun N-terminal kinase (JNK) that may subsequently activate c-Jun and may also interact with hypoxiainducible factor 1 (Hif-1) (14 -17). Other cellular responses involve transcriptional changes in hypoxia-responsive genes by Hif-1 and AP-1 (18 -21). The transcription factor AP1 is a homodimer/heterodimer formed by c-Jun and c-Jun/c-Jun and c-Fos or ATF-2 etc. However, there is no firm evidence to date indicating the linkage of hypoxia-induced AP-1/c-Jun activation to a particular signaling pathway.Mammalian cells from different tissues contain at least four Polo-like kinases (Plk1, Plk2, Plk3, and Plk4) that exhibit marked sequence homology to Drosophila Polo (22-26). As cells progress through the cell cycle, Plk proteins undergo substantial changes in abundance, kinase activity, or subcellular localization. Plk3 shares one or two stretches of conserved amino acid sequences termed Polo box, and contains similar phospho-serine/threonine-containing motifs for interactions with phosphoserine and phosphothreonine. Plk3 is a multifunctional protein and involves stress-induced signaling pathways in various cell types (27)(28)(29)(30). Plk3 proteins are rapidly activated upon stress stimulation including ionizing radiation (IR), ROS, and methylmethane sulfonate (MMS) (31). Plk3 is predominantly localized around the nu...

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confidence: 99%

Activation of Polo-like Kinase 3 by Hypoxic Stresses

Wang

Gao

Dai

et al. 2008

Journal of Biological Chemistry

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“…Targeting angiogenesis with adenovirally delivered inhibitors of VEGF production might also be used as a treatment of angiogenesis-related diseases in the cornea. The angiogenic process has been shown to be driven by increased secretion of VEGF [23,24,25]. …”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Curcumin on Corneal Neovascularization in vitro and in vivo

Bian¹,

Zhang²,

Zhu

2008

Ophthalmologica

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Purpose: To examine the effect of curcumin on the proliferation and the migration of human umbilical vein endothelial cells (HUVECs) and on the corneal neovascularization in the corneal alkaline burn rat model. Methods: HUVEC proliferation, migration, and apoptosis were examined after treatment with various concentrations of curcumin. The effect of curcumin on the activation of nuclear factor-ĸB (NF-ĸB) was measured by an electrophoretic mobility shift assay (EMSA) in vivo. Corneal neovascularization was induced in vivo by an alkaline burn of the cornea in Sprague-Dawley rats. After topical drug treatments with curcumin, vascular endothelial growth factor (VEGF) was evaluated in the corneal tissue by reverse transcription polymerase chain reaction and by immunohistochemistry. Corneal neovascularization was evaluated by slit-lamp biomicroscopy. Results: Curcumin at a concentration of 40 µmol/l for 24 h significantly inhibited the growth of HUVECs. The Boyden microchamber assay showed that curcumin dramatically inhibited the migration of HUVECs at a concentration of 40 µmol/l. When TUNEL assays were performed, the number of apoptotic cells increased after treated with curcumin. The EMSA revealed that curcumin inhibits the activation of NF-ĸB in HUVECs. The expression of VEGF in the corneal tissues was inhibited by curcumin on days 7 and 14 after alkaline burn. Conclusions: Curcumin may be useful as an angiogenic inhibitor in the treatment of corneal diseases that show neovascularization.

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“…89 Adenovirus-mediated transduction of corneal ECs with soluble VEGFR-1 successfully inhibited corneal neovascularisation in a rodent model. 90 The same group also used adenoassociated virus to reduce the development of 92 This group was also able to show viability gene transfer for the same receptor using a non-viral vector. 93 Another non-viral method employed experimentally for corneal antiangiogenic gene therapy was electroporation.…”

Section: Future Therapies May Rely On Local Gene Therapy To Influencementioning

confidence: 99%

Emerging techniques to treat corneal neovascularisation

Menzel‐Severing

2011

Eye

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Neovascularisation is a major cause of visual loss in a number of ophthalmic diseases. This review aims to outline the basic regulators of vessel growth in corneal neovascularisation. An understanding of the underlying principles of physiological and pathophysiological vascular development helps to appreciate current approaches to prevent or treat corneal neovascularisation. Options for future interventions will be discussed in the light of recent evidence provided by animal models of corneal neovascularisation.

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Flt-1 Intraceptors Inhibit Hypoxia-Induced VEGF Expression In Vitro and Corneal Neovascularization In Vivo

Cited by 66 publications

References 38 publications

Activation of Polo-like Kinase 3 by Hypoxic Stresses

Activation of Polo-like Kinase 3 by Hypoxic Stresses

Inhibitory Effect of Curcumin on Corneal Neovascularization in vitro and in vivo

Emerging techniques to treat corneal neovascularisation

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