title: Inhibition of neutral sphingomyelinase decreases elevated levels of inducible nitric oxide synthase and apoptotic cell death in ocular hypertensive rats.
abstract: Endoplasmic reticulum (ER) stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS2) have been implicated in the pathogenesis of neuronal retinal cell death in ocular hypertension. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression, hence this study determined the role of selective neutral sphingomyelinase (N-SMase) inhibition on retinal NOS2 levels, ER stress, apoptosis and visual evoked potentials (VEPs) in a rat model of elevated intraocular pressure (EIOP). NOS2 expression and retinal protein nitration were significantly greater in EIOP and significantly decreased with N-SMase inhibition. A significant increase was observed in retinal ER stress markers pPERK, CHOP and GRP78 in EIOP, which were not significantly altered by N-SMase inhibition. Retinal TUNEL staining showed increased apoptosis in all EIOP groups; however N-SMase inhibition significantly decreased the percent of apoptotic cells in EIOP. Caspase-3, -8 and -9 activities were significantly increased in EIOP and returned to baseline levels following N-SMase inhibition. Latencies of all VEP components were significantly prolonged in EIOP and shortened following N-SMase inhibition. Data confirm the role of nitrative injury in EIOP and highlight the protective effect of N-SMase inhibition in EIOP via down-regulation of NOS2 levels and nitrative stress.
authors.affiliation: Department of Medical Biochemistry, Akdeniz University Faculty of Medicine, Antalya, Turkey. Electronic address: mutayaslan@akdeniz.edu.tr.
authors.forename: Mutay
authors.initials: M
authors.lastname: Aslan
authors.affiliation: Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya, Turkey.
authors.forename: Goksun
authors.initials: G
authors.lastname: Basaranlar
authors.affiliation: Department of Ophthalmology, Akdeniz University Faculty of Medicine, Antalya, Turkey.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Unal
authors.affiliation: Department of Pathology, Akdeniz University Faculty of Medicine, Antalya, Turkey.
authors.forename: Akif
authors.initials: A
authors.lastname: Ciftcioglu
authors.affiliation: Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya, Turkey.
authors.forename: Narin
authors.initials: N
authors.lastname: Derin
authors.affiliation: Department of Chemistry & Biochemistry, University of Windsor, Windsor, Ontario, Canada.
authors.forename: Bulent
authors.initials: B
authors.lastname: Mutus
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001597:Benzylidene Compounds / Q000494:pharmacology; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005074:Evoked Potentials, Visual / Q000502:physiology; D005901:Glaucoma / Q000201:enzymology / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007429:Intraocular Pressure / Q000502:physiology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011897:Random Allocation; D017208:Rats, Wistar; D012160:Retina / Q000201:enzymology / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D000814:Aniline Compounds; D001597:Benzylidene Compounds; C468773:GW 4869; D052247:Nitric Oxide Synthase Type II; D013108:Sphingomyelin Phosphodiesterase; D020169:Caspases
keywords: Caspase; Endoplasmic reticulum stress; Inducible nitric oxide synthase; Neutral sphingomyelinase; Ocular hypertension; Protein nitration