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M. DeNiro, A. Al-Halafi, F. H. Al-Mohanna, O. Alsmadi, F. A. Al-Mohanna; Dual Targeting of Retinal Vasculature: YC-1 Selectively Mediates Retinal Vascular Remodeling in the Ischemic Retina and Exhibits Potent Inhibitory Effects on Retinal Neovascularization in a Mouse Model of OIR. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5906.
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Retinal ischemia has been shown to induce VEGF and iNOS expression. It has been postulated that one of the crucial consequences of iNOS expression in the ischemic retina, is the inhibition of angiogenesis. In addition, iNOS was shown to be overexpressed in Müller cells from patients with nonproliferative diabetic retinopathy. YC-1, a small molecule inhibitor of HIF-1, has exhibited potent iNOS-inhibitory effects in various tissue models.
An array of assays to evaluate the inhibitory effects of YC-1 on; (1) iNOS expression; (2) and retinal neovascularization (NV); in vitro (Müller and retinal neurosensory cells), and in vivo (OIR mouse model). Furthermore, we assessed the influence of YC-1 in the vascular repair promotion.
Dual injections of YC-1 into the neovascular retinas significantly decreased the total retinopathy score, inhibited vaso-obliteration and pathologic tuft formation, while concomitantly promoting physiological retinal revascularization. Moreover, YC-1-treated retinas exhibited a marked increase in vessels immunoreactivities for PECAM-1 and vWF, and displayed significant inhibition in HIF-1α protein expression. YC-1 down-regulated VEGF, EPO, ET-1, MMP-9, and iNOS message and protein levels. Furthermore, YC-1 dose dependently reduced iNOS mRNA and protein levels in hypoxic Müller and retinal neurosensory cells.
We demonstrate that YC-1 enhanced physiological revascularization of the retinal vascular plexus via exerting a potent inhibitory influence on iNOS mRNA and protein expressions. Furthermore, YC-1 inhibited pathological retinal neovascularization via exhibiting effective anti-angiogenic and anti-neovascular properties, which impaired ischemia-induced expression of HIF-1 and its downstream angiogenic molecules. The effects of YC-1 allude to its potential therapeutic use as a promising therapeutic iNOS inhibitor candidate for the treatment of neovascular retinal diseases.
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