autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressureautotaxin-lysophosphatidic酸轴是一种新型的分子目标降低眼压.pdfVIP

Autotaxin-Lysophosphatidic Acid Axis Is a Novel Molecular Target for Lowering Intraocular Pressure 1 1 1 1 1 1,2 Padma Iyer , Robert Lalane III , Corey Morris , Pratap Challa , Robin Vann , Ponugoti Vasantha Rao * 1 Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, United States of America, 2 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, United States of America Abstract 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 m