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M. DeNiro, F. Al-Mohanna, O. AlSmadi, A. Al-Halafi, F. Al-Mohanna; Pleiotropic Effects of YC-1 Attenuates Pathological Retinal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2009;50(13):41.
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© ARVO (1962-2015); The Authors (2016-present)
We exploited hypoxia to assess the effects of YC-1, a HIF-1 inhibitor on retinal neovascularization; in vitro, ex vivo and in vivo.
We used an array of assays to investigate the antiangiogenic effect(s) of YC-1 in human retinal microvascular endothelial cells (HRMVEC), retinal explants, and oxygen-induced retinopathy mouse model (OIR).
YC-1 decreased the basal HIF-1 protein levels under normoxia and suppressed HIF-1 protein synthesis and nuclear translocation under hypoxia in HRMVEC. Furthermore, YC-1 inhibited the message and protein levels of HIF-2, VEGF, EPO, ET-1, and MMP-9. It suppressed the MMP-9 activity, whereas it enhanced the proteasome activity and induced a G0/G1 cell arrest, with negligible apoptotic activity. Furthermore, YC-1 inhibited cell proliferation, migration, wound healing, tube formation, and diminished the neovascular sprouts outgrowth from retinal explants. In the mouse OIR, intravitreal injections of YC-1 significantly reduced the angioproliferative changes, blood vessel tortuosity and neovascular tufts. The median retinopathy score for the YC-1-treated group eyes was significantly reduced as compared to controls. Immunohistochemistry staining showed a significant reduction in CD31 and Factor VIII staining in YC-1-treated retinae compared with controls. Whereas the mRNA levels for HIF-1 remained unchanged in response to YC-1, the message and the protein levels of HIF-2, VEGF, EPO, ET-1, and MMP-9 were significantly inhibited.
Our study exhibits the antiangiogenic potential of YC-1 in the treatment of retinal neovascularization; in vitro, ex vivo, and in vivo. We demonstrate that YC-1 impedes the development of angiogenic stimuli induced neovascularization in the retina. Our observations raise the possibility that YC-1 may have a therapeutic potential as a potent antiangiogenic agent in the treatment of retinal neovascularization.
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