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Suppression of Acid Sphingomyelinase Protects the Retina from Ischemic Injury.
- Source :
-
Investigative ophthalmology & visual science [Invest Ophthalmol Vis Sci] 2016 Aug 01; Vol. 57 (10), pp. 4476-84. - Publication Year :
- 2016
-
Abstract
- Purpose: Acid sphingomyelinase (ASMase) catalyzes the hydrolysis of sphingomyelin to ceramide and mediates multiple responses involved in inflammatory and apoptotic signaling. However, the role ASMase plays in ischemic retinal injury has not been investigated. The purpose of this study was to investigate how reduced ASMase expression impacts retinal ischemic injury.<br />Methods: Changes in ceramide levels and ASMase activity were determined by high performance liquid chromatography-tandem mass spectrometry analysis and ASMase activity. Retinal function and morphology were assessed by electroretinography (ERG) and morphometric analyses. Levels of TNF-α were determined by ELISA. Activation of p38 MAP kinase was assessed by Western blot analysis.<br />Results: In wild-type mice, ischemia produced a significant increase in retinal ASMase activity and ceramide levels. These increases were associated with functional deficits as measured by ERG analysis and significant structural degeneration in most retinal layers. In ASMase+/- mice, retinal ischemia did not significantly alter ASMase activity, and the rise in ceramide levels were significantly reduced compared to levels in retinas from wild-type mice. In ASMase+/- mice, functional and morphometric analyses of ischemic eyes revealed significantly less retinal degeneration than in injured retinas from wild-type mice. The ischemia-induced increase in retinal TNF-α levels was suppressed by the administration of the ASMase inhibitor desipramine, or by reducing ASMase expression.<br />Conclusions: Our results demonstrate that reducing ASMase expression provides partial protection from ischemic injury. Hence, the production of ceramide and subsequent mediators plays a role in the development of ischemic retinal injury. Modulating ASMase may present new opportunities for adjunctive therapies when treating retinal ischemic disorders.
- Subjects :
- Animals
Apoptosis
Blotting, Western
Ceramides metabolism
Chromatography, High Pressure Liquid
Disease Models, Animal
Electroretinography
Enzyme Inhibitors pharmacology
Enzyme-Linked Immunosorbent Assay
Mice, Inbred C57BL
Mice, Knockout
Reperfusion Injury complications
Reperfusion Injury metabolism
Retina diagnostic imaging
Retina physiopathology
Retinal Degeneration diagnosis
Retinal Degeneration etiology
Signal Transduction
Sphingomyelin Phosphodiesterase metabolism
Tumor Necrosis Factor-alpha metabolism
Desipramine pharmacology
Reperfusion Injury prevention & control
Retina drug effects
Retinal Degeneration prevention & control
Sphingomyelin Phosphodiesterase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1552-5783
- Volume :
- 57
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Investigative ophthalmology & visual science
- Publication Type :
- Academic Journal
- Accession number :
- 27571014
- Full Text :
- https://doi.org/10.1167/iovs.16-19717