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Fei Zhao, Qingyi Zhou, Ying Zhai, Jia Qu, Xiangtian Zhou; Sclera-specific Hif-1α knockdown attenuates form deprivation myopia (FDM) development in mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5898. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Hypoxia contributes to myopia development in form deprived (FD) mice and guinea pigs through promoting myofibroblast transdifferentiation and suppressing collagen synthesis, whereas two hypoxia inhibitors slowed FDM development. To confirm the role of hypoxia in myopia development, we determined the effect of sclera-specific hypoxia inducible factor-1α (Hif-1α) knockdown on scleral remodeling and FDM development in mice.
To generate sclera-specific Hif-1α knockdown mice, Hif-1αfl/fl mice were injected with an AAV8-packaged Cre overexpressing vector (AAV8-Cre) in the sub-Tenon’s capsule. The effects of scleral Hif-1α knockdown on myopia development were evaluated in 4-week-old Hif-1αfl/fl mice. They were randomly assigned to three different groups: mice injected with either AAV8-Cre overexpression vector or AAV8-package empty vector, and after a week FDM was initiated for the next 2 weeks (AAV8-Cre+FD and AAV8-vector+FD). Non-injected mice subjected to FDM served as the controls (Control+FD). Refraction and ocular biometric parameters were measured before and 2 weeks after FD (weeks 5 and 9). Western blot analysis determined protein expression levels of Hif-1α and Col1α1. α-SMA measurements assessed myofibroblast transdifferentiation.
Consistent with our previous study, after 2 weeks of form deprivation, Hif-1α protein expression was significantly higher in FD treated (FD-T) eyes than in untreated fellow (FD-F) eyes of the AAV8-Vector+FD group. In contrast, this increase was suppressed in FD-T eyes of AAV8-Cre+FD mice compared with FD-T eyes of AAV8-Vector+FD mice. AAV8-Vector+FD mice exhibited significantly higher α-SMA expression and lower Col1α1 expression in FD-T eyes than in FD-F eyes. These protein expression level changes were inhibited in FD-T eyes of AAV8-Cre+FD mice compared with FD-T eyes of AAV8-Vector+FD mice. After 2 weeks of form deprivation, significant myopia was induced in the Control+FD and AAV8-Vector+FD groups but not in the AAV8-Cre+FD group. Myopia development was significantly suppressed in these sclera-specific Hif-1α knockdown mice. In parallel with refraction changes, AL and VCD increases were also significantly less in AAV8-Cre+FD mice than in AAV8-Vector+FD mice.
These results thus indicate that reducing scleral Hif-1α expression levels attenuate myopia development in a form deprivation mouse model.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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