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Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure.

Publication ,  Journal Article
Iyer, P; Lalane, R; Morris, C; Challa, P; Vann, R; Rao, PV
Published in: PLoS One
2012

Primary open-angle glaucoma is the second leading cause of blindness in the United States and is commonly associated with elevated intraocular pressure (IOP) resulting from diminished aqueous humor (AH) drainage through the trabecular pathway. Developing effective therapies for increased IOP in glaucoma patients requires identification and characterization of molecular mechanisms that regulate IOP and AH outflow. This study describes the identification and role of autotaxin (ATX), a secretory protein and a major source for extracellular lysophosphatidic acid (LPA), in regulation of IOP in a rabbit model. Quantitative proteomics analysis identified ATX as an abundant protein in both human AH derived from non-glaucoma subjects and in AH from different animal species. The lysophospholipase D (LysoPLD) activity of ATX was found to be significantly elevated (by ∼1.8 fold; n=20) in AH derived from human primary open angle glaucoma patients as compared to AH derived from age-matched cataract control patients. Immunoblotting analysis of conditioned media derived from primary cultures of human trabecular meshwork (HTM) cells has confirmed secretion of ATX and the ability of cyclic mechanical stretch of TM cells to increase the levels of secreted ATX. Topical application of a small molecular chemical inhibitor of ATX (S32826), which inhibited AH LysoPLD activity in vitro (by >90%), led to a dose-dependent and significant decrease of IOP in Dutch-Belted rabbits. Single intracameral injection of S32826 (∼2 µM) led to significant reduction of IOP in rabbits, with the ocular hypotensive response lasting for more than 48 hrs. Suppression of ATX expression in HTM cells using small-interfering RNA (siRNA) caused a decrease in actin stress fibers and myosin light chain phosphorylation. Collectively, these observations indicate that the ATX-LPA axis represents a potential therapeutic target for lowering IOP in glaucoma patients.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

8

Start / End Page

e42627

Location

United States

Related Subject Headings

  • Trabecular Meshwork
  • Rabbits
  • RNA, Small Interfering
  • Proteomics
  • Phosphoric Diester Hydrolases
  • Organophosphonates
  • Models, Animal
  • Lysophospholipids
  • Intraocular Pressure
  • Humans
 

Citation

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Chicago
ICMJE
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Iyer, P., Lalane, R., Morris, C., Challa, P., Vann, R., & Rao, P. V. (2012). Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure. PLoS One, 7(8), e42627. https://doi.org/10.1371/journal.pone.0042627
Iyer, Padma, Robert Lalane, Corey Morris, Pratap Challa, Robin Vann, and Ponugoti Vasantha Rao. “Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure.PLoS One 7, no. 8 (2012): e42627. https://doi.org/10.1371/journal.pone.0042627.
Iyer P, Lalane R, Morris C, Challa P, Vann R, Rao PV. Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure. PLoS One. 2012;7(8):e42627.
Iyer, Padma, et al. “Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure.PLoS One, vol. 7, no. 8, 2012, p. e42627. Pubmed, doi:10.1371/journal.pone.0042627.
Iyer P, Lalane R, Morris C, Challa P, Vann R, Rao PV. Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure. PLoS One. 2012;7(8):e42627.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

8

Start / End Page

e42627

Location

United States

Related Subject Headings

  • Trabecular Meshwork
  • Rabbits
  • RNA, Small Interfering
  • Proteomics
  • Phosphoric Diester Hydrolases
  • Organophosphonates
  • Models, Animal
  • Lysophospholipids
  • Intraocular Pressure
  • Humans