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Therapeutic potential of topical administration of siRNAs against HIF-1α for corneal neovascularization



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Peral Cerdá, Assumpta and Mateo Ibáñez, Jesús and Dominguez Godínez, Carmen Olalla and Carracedo Rodríguez, Juan Gonzalo and Gómez Pedrero, José Antonio and Crooke, Almudena and Pintor, Jesús (2022) Therapeutic potential of topical administration of siRNAs against HIF-1α for corneal neovascularization. Experimental Eye Research, 219 . art. 109036. ISSN 0014-4835

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Official URL: https://doi.org/10.1016/j.exer.2022.109036


Given the implications of the problem of neovascularization on ocular health, as well as the growth in the number of cases, the purpose of the present study has been testing the efficacy of siRNAs (small interfering RNA) designed to silence Hypoxia Inducible Factor -1α (HIF-1α) and to demonstrate that their use stops neovascularization in a model of corneal burn.

Corneal wounds in the limbic zone were made in the eyes of New Zealand white rabbits. Topical applications of siRNAs were done the next day to the wound for four consecutive days and eyes were examined with a slit lamp. Evaluation of neovascularization progress was done by analyzing images by ImageJTM and to determine the neovascular area in Matlab ® was used. At the same time, a rabbit corneal cell line was used for in vitro study of hypoxia exposure and Western blot analysis of the cell's extracts were done.

Under normal cell culture oxygenation, the expression of HIF-1α was lower than that observed under hypoxic conditions. After 2 h of hypoxia, there was a significant increase in the HIF-1α expression, effect that was maintained up to 6 h. The increased in HIF-1α was mimicked by a cell permeable prolyl-4-hydroxylase inhibitor. Cobalt chloride showed no capacity to increase HIF-1α in vitro. The effect of three different siRNA on HIF-1α was tested after 4 h of hypoxia. siRNA#1 was able to silence 80% of HIF-1α expression, siRNA#2 and siRNA#3 reduce the expression in 45% and 40% respectively.

In addition, the three siRNA were tested in a corneal model of neovascularization. scrambledsiRNA#2 was the most effective inhibitor of blood vessel production, followed by siRNA#3 and siRNA#1. Compared to the scrambled siRNA (100% of blood vessel generation), siRNA#2 blocked the presence of blood vessels by 83 ± 2%, siRNA#3 inhibited 45 ± 7% and siRNA#1 only inhibited 18 ± 5%. The necessary time to observe the 50% of effect showed values of NV50 of 10.2 ± 2.4 days for the scrambled siRNA, 9.1 ± 1.4 for siRNA#1, 6.5 ± 1.85 for siRNA#2 and 4.8 ± 1.8 days for siRNA#3. In conclusion, the topical application of siRNA towards HIF-1α seems to be an effective and reliable method to stop neovascularization.

Item Type:Article
Additional Information:

Received 5 November 2021, Revised 19 February 2022, Accepted 12 March 2022, Available online 31 March 2022, Version of Record 2 April 2022.

Uncontrolled Keywords:Blood vessel; Cornea; HIF-1α; Hypoxia; Neovascularization; siRNA
Subjects:Medical sciences > Medicine > Pharmacology
Medical sciences > Medicine > Ophtalmology
ID Code:76378
Deposited On:08 Feb 2023 20:16
Last Modified:08 Feb 2023 20:16

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