Abstract
(R,R) ZX-5 has been proven to have positive effects on choroidal blood flow without affecting the sclera and ciliary bodies in New Zealand white rabbits. This study was designed to investigate the mechanisms of (R,R) ZX-5 on improving the choroidal blood flow and promoting NO production. HUVECs (human umbilical vein endothelial cells) were used to determine the production of eNOS, p-eNOS, AKT and Erk1/2 by Western blot analysis. iNOS and eNOS mRNA levels were investigated by RT-PCR and the effect of (R,R) ZX-5 on NO production were determined by eNOS activity assay. We found (R,R) ZX-5 upregulated protein expression of eNOS and iNOS, increased NO production, and reduced ERK and Akt protein level. Therefore, (R,R) ZX-5 may promote the choroidal blood flow in New Zealand white rabbits without affecting the blood flow in the iris or ciliary bodies via increasing NO production. These results suggest that (R,R) ZX-5 may function to cure and prevent Age-related macular degeneration (AMD).
Highlights
Age-related macular degeneration (AMD) is a progressive disease affecting nearly 50 million people worldwide [1,2]
The development of choroidal neovascularization (CNV) has been linked to dysregulation of intercellular signaling molecules, such as nitric oxide (NO) [1,2,3], a key signaling messenger, which is synthesized in mammalian tissues by three distinct isoforms of NO synthase (NOS): neuronal NOS, endothelial NOS, and inducible NOS
Insufficient NO production due to inadequate NOS activity can lead to various eye diseases, including AMD; consistent with this, increasing NOS activity can provide NO donors to the eyes, lower the intraocular pressure, increase ocular blood flow, and relax ciliary muscle [3]
Summary
Age-related macular degeneration (AMD) is a progressive disease affecting nearly 50 million people worldwide [1,2]. It causes irreversible visual impairment and blindness which can be largely attributed to choroidal neovascularization (CNV), the development of abnormal blood vessels underneath the retina. We have designed and produced more than 200 NOS regulators, and one of them, (R, R)ZX-5, has been demonstrated to promote the blood flow of choroid but not sclera and cilliary bodies in New. Zealand white rabbits [4]. The trans-form of the compound, (S,S) ZX-5, does not display any effects on the choroidal blood flow in New Zealand white rabbit [4], indicating that the choroidal blood flow promoting effect is (R,R) ZX-5 specific. We examined the role of (R,R) ZX-5 on the expression of eNOS and iNOS, and the possible signal molecules ERK and Akt, determinant of NO production
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