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A fragment of human TrpRS as a potent antagonist of ocular angiogenesis
Atsushi Otani1, Bonnie M Slike, Michael I Dorrell
1Department of Cell Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
Pathological angiogenesis contributes directly to profound loss of vision associated with many diseases of the eye. Recent work suggests that human tyrosyl- and tryptophanyl-tRNA synthetases (TrpRS) link protein synthesis to signal transduction pathways including angiogenesis. In this study, we show that a recombinant form of a COOH-terminal fragment of TrpRS is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in a mouse model and of naturally occurring retinal angiogenesis in the neonatal mouse. The angiostatic activity is dose-dependent in both systems. The recombinant fragment is similar in size to one generated naturally by alternative splicing and can be produced by proteolysis of the full-length protein. In contrast, the full-length protein is inactive as an antagonist of angiogenesis. These results suggest that fragments of TrpRS, as naturally occurring and potentially nonimmunogenic anti-angiogenics, can be used for the treatment of neovascular eye diseases.
Insights
A novel fragment of human tryptophanyl-tRNA synthetase (TrpRS) effectively inhibits pathological angiogenesis in mouse models. This finding suggests potential new treatments for neovascular eye diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Biochemistry
Background:
- Pathological angiogenesis is a major cause of vision loss in various eye diseases.
- Human tyrosyl- and tryptophanyl-tRNA synthetases (TrpRS) are implicated in linking protein synthesis to angiogenesis.
- Understanding the role of TrpRS in angiogenesis is crucial for developing novel therapies.
Purpose of the Study:
- To investigate the anti-angiogenic potential of a COOH-terminal fragment of human TrpRS.
- To evaluate the efficacy of this fragment in inhibiting both vascular endothelial growth factor-induced and naturally occurring retinal angiogenesis.
- To determine if the full-length TrpRS protein exhibits similar anti-angiogenic activity.
Main Methods:
- Utilized a recombinant COOH-terminal fragment of human TrpRS.
- Tested the fragment's efficacy in a mouse model of vascular endothelial growth factor-induced angiogenesis.
- Assessed the fragment's activity in a neonatal mouse model of naturally occurring retinal angiogenesis.
- Compared the anti-angiogenic activity of the fragment with the full-length TrpRS protein.
Main Results:
- The recombinant TrpRS fragment demonstrated potent, dose-dependent antagonism of angiogenesis in both tested mouse models.
- The anti-angiogenic activity was observed in both induced and naturally occurring retinal angiogenesis.
- The full-length TrpRS protein did not show antagonist activity against angiogenesis.
- The active fragment is comparable in size to one produced by alternative splicing or proteolysis.
Conclusions:
- Fragments of TrpRS, particularly the COOH-terminal portion, act as effective anti-angiogenics.
- These naturally occurring fragments may offer a therapeutic strategy for neovascular eye diseases.
- The potential non-immunogenic nature of these fragments is advantageous for therapeutic applications.
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