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Leona Ho, Anja Osterwald, Solveig Badillo, Iris Ruf, Pratap Challa, Robin Vann, Vasanth Rao, Christoph Ullmer; Dysregulation of the Autotaxin/LPA Signaling Axis in the Aqueous Humor of Human Glaucoma Patients.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4715.
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Lysophosphatidic acid (LPA), a well-characterized lipid growth factor and autotaxin (ATX), a secretory enzyme and primary source for the generation of LPA from lysophosphatidylcholine (LPC), have been shown to modulate aqueous humor (AH) outflow and intraocular pressure (IOP). In order to further elaborate the link of the ATX/LPA axis to ocular hypertension in glaucoma, we investigated the regulation of ATX within human trabecular meshwork (TM), and if the levels of LPA and/or ATX are dysregulated in the AH of glaucoma patients.
The levels of ATX, LPA, and LPC in AH derived from primary open-angle glaucoma, and age- and gender-matched cataract (control) patients (n=25), were measured by ELISA and mass spectrometry. The regulation of ATX protein levels in primary human TM cell cultures (n=4-6) by different physiological agents was determined by immunoblot analysis.
ELISA based analysis showed a significant increase (by >50%) in the levels of ATX protein in the AH of glaucoma patients relative to AH from cataract patients. Additionally, elevated levels of ATX protein in the AH from glaucoma patients were found to exhibit a positive correlation (p <0.007) with IOP values in these patients. Moreover, mass spectrometry analysis of AH revealed significant (p<0.001) increase in both LPA (16:0 & 18:1) and LPC (16:0, 18:0 & 18:1) levels in the glaucoma samples compared to cataract samples. ATX protein levels were significantly (p<0.05) elevated in human primary TM cell lysates and conditioned media in response to treatment with dexamethasone (0.5 μM, 96 hr), TNF-α (10 ng/ml, 24 hr), or IL-1β (10 ng/ml, 24 hr), and by cyclic mechanical stretch, relative to untreated control TM cells.
Collectively, these results, together with the previously reported observations on the elevated ATX activity in the AH from glaucoma patients, confirm and establish an association between dysregulated levels of ATX, LPA, and LPC and the etiology of ocular hypertension in primary open-angle glaucoma patients. Moreover, several physiological agents known to elevate IOP were also found to increase the levels of ATX in human TM cells. These observations support the exploration of the ATX/LPA axis targeted therapies for the treatment of ocular hypertension in glaucoma patients.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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