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Leona Ho, Nikolai Skiba, Christoph Ullmer, P Vasanth Rao; Role of the Autotaxin-Lysophosphatidic Acid Signaling Axis in Trabecular Meshwork and Homeostasis of Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5626.
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© ARVO (1962-2015); The Authors (2016-present)
Lysophosphatic acid (LPA), a bioactive lipid produced by autotaxin (ATX) exerts a broad range of cellular effects through multiple G protein-coupled receptors (LPARs) and influences a wide range of physiological and pathological processes. Significantly, both LPA and ATX have been demonstrated to modulate aqueous humor outflow and intraocular pressure (IOP); however, our knowledge regarding the effects of LPA on human trabecular meshwork (HTM) cell biology is limited. In this study, we undertook a comprehensive investigation of LPA induced changes in HTM cell contractile activity, cell adhesive interactions and mechanotransduction.
The expression profile of LPA receptors (LPARs), LPA hydrolyzing lipid phosphate phosphatases (LPPs), and ATX was determined in HTM cells under both normal and cyclic mechanical stretch by qRT-PCR analysis. The effects of LPA and selective LPAR antagonists on HTM cell contractile properties, adhesive interactions, mechanotransduction, extracellular matrix (ECM) protein expression and fibrogenic activity were evaluated by immunoblot blot, immunofluorescence, mass spectrometry analyses.
HTM cells express relatively abundant levels of LPAR1, LPAR3 and LPAR6 along with LPP1-3. Cyclic mechanical stretch (15% for 24 hrs) significantly increased the expression of LPAR1, LPAR3, LPP1 and ATX. Mechanistic studies revealed the involvement of Rho-kinase, protein kinase C and myosin light kinase in LPA-induced changes in HTM cell contractile (myosin light chain phosphorylation) and adhesive properties (phospho-paxillin, phospho-focal adhesion kinase and Hic-5). LPA also triggered significant levels of fibrogenic factors (CYR61 and CTGF) through the YAP/TAZ mechanotransduction pathway and ECM production in TM cells. Additionally, pharmacological inhibition of LPAR1 and 3 in TM cells suppressed the profibrotic and contractile activity.
Taken together these results demonstrate that mechanical stretch of HTM cells influences expression of LPARs, LPPs and ATX, and LPA-induced HTM cell contractile activity, cell adhesion, ECM production and profibrotic factors appeared to be mediated through independent intracellular mechanisms downstream to LPAR1-3 involving Rho kinase, PKC, MLC kinase and Yap and TAZ. Importantly, these observations further support targeting of the ATX-LPA signaling axis to lower IOP in glaucoma patients.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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