title: Inhibition of Matrix Metalloproteinase 9 Enhances Rod Survival in the S334ter-line3 Retinitis Pigmentosa Model.
abstract: Retinitis Pigmentosa (RP) is one of the most common forms of inherited visual loss with the initial degeneration of rod photoreceptors, followed by a progressive cone photoreceptor deterioration. Coinciding with this visual loss, the extracellular matrix (ECM) is reorganized, which alters matrix metalloproteinase (MMP) activity levels. A potential pathological role of MMPs, MMP-9 in particular, involves an excitotoxicity-mediated physiological response. In the current study, we examine the MMP-9 and MMP-2 expression levels in the rhodopsin S334ter-line3 RP rat model and investigate the impact of treatment with SB-3CT, a specific MMP-9 and MMP-2 inhibitor, on rod cell survival was tested. Retinal MMP-9 and MMP-2 expression levels were quantified by immunoblot analysis from S334ter-line3 rats compared to controls. Gelatinolytic activities of MMP-9 and MMP-2 by zymography were examined. The geometry of rod death was further evaluated using Voronoi analysis. Our results revealed that MMP-9 was elevated while MMP-2 was relatively unchanged when S334ter-line 3 retinas were compared to controls. With SB-3CT treatment, we observed gelatinolytic activity of both MMPs was decreased and diminished clustering associated with rod death, in addition to a robust preservation of rod photoreceptors. These results demonstrate that up-regulation of MMP-9 in retinas of S334ter-line3 are associated with rod death. The application of SB-3CT dramatically interferes with mechanisms leading to apoptosis in an MMP-9-dependent manner. Future studies will determine the feasibility of using SB-3CT as a potential therapeutic strategy to slow progression of vision loss in genetic inherited forms of human RP.
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.|Department of Anatomy, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jung-A
authors.initials: JA
authors.lastname: Shin
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.
authors.forename: Hwa Sun
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Vargas
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.|Department of Biological Structure, University of Washington, Seattle, Washington, United States of America.
authors.forename: Wan-Qing
authors.initials: WQ
authors.lastname: Yu
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.
authors.forename: Yun Sung
authors.initials: YS
authors.lastname: Eom
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.|Department of Cell & Neurobiology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.|Neuroscience Graduate Program, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Cheryl Mae
authors.initials: CM
authors.lastname: Craft
authors.affiliation: Mary D. Allen Laboratory for Vision Research, USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States of America.|Department of Biomedical Engineering, University of Southern California Viterbi School of Engineering, Los Angeles, California, United States of America.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000201:enzymology; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D012174:Retinitis Pigmentosa / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D011480:Protease Inhibitors; C429533:SB 3CT compound; D013450:Sulfones; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat