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• W2901787968 abstract "Over 11 million people in the United States alone have some form of age-related macular degeneration (AMD). Oxidative stress, cell death, and the degeneration of retinal pigment epithelial (RPE) cells contribute to AMD pathology. Recent evidence suggests that ceramide (Cer), a cellular sphingolipid mediator that acts as a second messenger to induce apoptosis, might play a role in RPE cell death. The lysosomal breakdown of Cer by acid ceramidase [N-acylsphingosine amidohydrolase (ASAH)1] into sphingosine (Sph) is the major source for Sph 1-phosphate production, which has an opposing role to Cer and provides cytoprotection. Here, we investigated the role of Cer in human RPE-derived ARPE19 cells under hydrogen peroxide-induced oxidative stress, and show that Cer and hexosyl-Cer levels increase in the oxidatively stressed ARPE19 cells, which can be prevented by overexpression of lysosomal ASAH1. This study demonstrates that oxidative stress generates sphingolipid death mediators in retinal cells and that induction of ASAH1 could rescue retinal cells from oxidative stress by hydrolyzing excess Cers. Over 11 million people in the United States alone have some form of age-related macular degeneration (AMD). Oxidative stress, cell death, and the degeneration of retinal pigment epithelial (RPE) cells contribute to AMD pathology. Recent evidence suggests that ceramide (Cer), a cellular sphingolipid mediator that acts as a second messenger to induce apoptosis, might play a role in RPE cell death. The lysosomal breakdown of Cer by acid ceramidase [N-acylsphingosine amidohydrolase (ASAH)1] into sphingosine (Sph) is the major source for Sph 1-phosphate production, which has an opposing role to Cer and provides cytoprotection. Here, we investigated the role of Cer in human RPE-derived ARPE19 cells under hydrogen peroxide-induced oxidative stress, and show that Cer and hexosyl-Cer levels increase in the oxidatively stressed ARPE19 cells, which can be prevented by overexpression of lysosomal ASAH1. This study demonstrates that oxidative stress generates sphingolipid death mediators in retinal cells and that induction of ASAH1 could rescue retinal cells from oxidative stress by hydrolyzing excess Cers. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population. More than 80% of AMD cases are of the dry-AMD classification, which characteristically features geographic atrophy resulting from the loss of retinal pigment epithelial (RPE) cells (1Young R.W. Pathophysiology of age-related macular degeneration.Surv. Ophthalmol. 1987; 31: 291-306Abstract Full Text PDF PubMed Scopus (516) Google Scholar, 2Hogan M.J. Role of the retinal pigment epithelium in macular disease.Trans. Am. Acad. Ophthalmol. Otolaryngol. 1972; 76: 64-80PubMed Google Scholar). Dry-AMD often converts to wet-AMD, which is vision-threatening. Accumulation of undigested cellular debris (e.g., drusen), oxidative stress, and subsequent death and degeneration of RPE cells are important contributors to AMD pathology (3Holz F.G. Bellman C. Staudt S. Schutt F. Volcker H.E. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration.Invest. Ophthalmol. Vis. Sci. 2001; 42: 1051-1056PubMed Google Scholar, 4Kennedy C.J. Rakoczy P.E. Constable I.J. Lipofuscin of the retinal pigment epithelium: a review.Eye (Lond.). 1995; 9: 763-771Crossref PubMed Scopus (301) Google Scholar). Accumulating evidence suggests that the cellular sphingolipid mediator, ceramide (Cer), which acts as a second messenger to induce apoptosis, might play a role in RPE cell death (5Tomita H. Abe T. Tamai M. Ceramide-induced cell death in cultured rat retinal pigment epithelial cells.Tohoku J. Exp. Med. 2000; 190: 223-229Crossref PubMed Scopus (9) Google Scholar, 6Kannan R. Jin M. Gamulescu M.A. Hinton D.R. Ceramide-induced apoptosis: role of catalase and hepatocyte growth factor.Free Radic. Biol. Med. 2004; 37: 166-175Crossref PubMed Scopus (58) Google Scholar, 7Barak A. Morse L.S. Goldkorn T. Ceramide: a potential mediator of apoptosis in human retinal pigment epithelial cells.Invest. Ophthalmol. Vis. Sci. 2001; 42: 247-254PubMed Google Scholar). Here, we investigate for the first time the role of Cer in human RPE-derived ARPE19 cells under oxidative stress by removing excess cellular Cer via genetic manipulation of Cer-hydrolyzing enzymes. In addition to being a critical component of membrane structure and function, Cer serves as a vital intracellular second messenger. A steady-state level of Cer is necessary for cell proliferation and differentiation (8Merrill Jr., A.H. Schmelz E.M. Dillehay D.L. Spiegel S. Shayman J.A. Schroeder J.J. Riley R.T. Voss K.A. Wang E. Sphingolipids–the enigmatic lipid class: biochemistry, physiology, and pathophysiology.Toxicol. Appl. Pharmacol. 1997; 142: 208-225Crossref PubMed Scopus (565) Google Scholar, 9Spiegel S. Merrill Jr., A.H. Sphingolipid metabolism and cell growth regulation.FASEB J. 1996; 10: 1388-1397Crossref PubMed Scopus (649) Google Scholar), while excessive amounts of Cer are often toxic and can result in cellular apoptosis (10Jarvis W.D. Grant S. The role of ceramide in the cellular response to cytotoxic agents.Curr. Opin. Oncol. 1998; 10: 552-559Crossref PubMed Scopus (39) Google Scholar). High concentrations of Cer can result in the induction of cell death, leading to tissue damage and organ failure, such as what is observed in retinal degeneration (RD) (11Chen H. Tran J.T. Eckerd A. Huynh T.P. Elliott M.H. Brush R.S. Mandal N.A. Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration.J. Lipid Res. 2013; 54: 1616-1629Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 12Chen H. Tran J.T. Brush R.S. Saadi A. Rahman A.K. Yu M. Yasumura D. Matthes M.T. Ahern K. Yang H. et al.Ceramide signaling in retinal degeneration.Adv. Exp. Med. Biol. 2012; 723: 553-558Crossref PubMed Scopus (27) Google Scholar), systemic lupus erythematosus (13Jiang P. Bian M. Ma W. Liu C. Yang P. Zhu B. Xu Y. Zheng M. Qiao J. Shuai Z. et al.Eryptosis as an underlying mechanism in systemic lupus erythematosus-related anemia.Cell. Physiol. Biochem. 2016; 40: 1391-1400Crossref PubMed Scopus (21) Google Scholar, 14Checa A. Idborg H. Zandian A. Sar D.G. Surowiec I. Trygg J. Svenungsson E. Jakobsson P.J. Nilsson P. Gunnarsson I. et al.Dysregulations in circulating sphingolipids associate with disease activity indices in female patients with systemic lupus erythematosus: a cross-sectional study.Lupus. 2017; 26: 1023-1033Crossref PubMed Scopus (30) Google Scholar), and diabetes mellitus (15Galadari S. Rahman A. Pallichankandy S. Galadari A. Thayyullathil F. Role of ceramide in diabetes mellitus: evidence and mechanisms.Lipids Health Dis. 2013; 12: 98Crossref PubMed Scopus (128) Google Scholar). In contrast, a continuous basal level of Cer is essential in staving off many neurodegenerative diseases, such as Parkinson's disease (16Xing Y. Tang Y. Zhao L. Wang Q. Qin W. Ji X. Zhang J. Jia J. Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinson's disease dementia.J. Neurol. Sci. 2016; 370: 82-87Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 17Abbott S.K. Li H. Munoz S.S. Knoch B. Batterham M. Murphy K.E. Halliday G.M. Garner B. Altered ceramide acyl chain length and ceramide synthase gene expression in Parkinson's disease.Mov. Disord. 2014; 29: 518-526Crossref PubMed Scopus (83) Google Scholar, 18Bienias K. Fiedorowicz A. Sadowska A. Prokopiuk S. Car H. Regulation of sphingomyelin metabolism.Pharmacol. Rep. 2016; 68: 570-581Crossref PubMed Scopus (95) Google Scholar) and Alzheimer's disease (18Bienias K. Fiedorowicz A. Sadowska A. Prokopiuk S. Car H. Regulation of sphingomyelin metabolism.Pharmacol. Rep. 2016; 68: 570-581Crossref PubMed Scopus (95) Google Scholar, 19Young S.A. Mina J.G. Denny P.W. Smith T.K. Sphingolipid and ceramide homeostasis: potential therapeutic targets.Biochem. Res. Int. 2012; 2012: 248135Crossref PubMed Scopus (42) Google Scholar, 20Katsel P. Li C. Haroutunian V. Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease?.Neurochem. Res. 2007; 32: 845-856Crossref PubMed Scopus (179) Google Scholar, 21de la Monte S.M. Re E. Longato L. Tong M. Dysfunctional pro-ceramide, ER stress, and insulin/IGF signaling networks with progression of Alzheimer's disease.J. Alzheimers Dis. 2012; 30 (Suppl. 2): S217-S229Crossref PubMed Scopus (65) Google Scholar). The generation of endogenous Cer is induced by noxious stimuli, such as UV A light (22Chatterjee M. Wu S. Cell line dependent involvement of ceramide in ultraviolet light-induced apoptosis.Mol. Cell. Biochem. 2001; 219: 21-27Crossref PubMed Scopus (31) Google Scholar) and proinflammatory cytokines (e.g., TNF-α) (23Dbaibo G.S. El-Assaad W. Krikorian A. Liu B. Diab K. Idriss N.Z. El-Sabban M. Driscoll T.A. Perry D.K. Hannun Y.A. Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death.FEBS Lett. 2001; 503: 7-12Crossref PubMed Scopus (95) Google Scholar), both of which promote the release of Cer from SM and/or by the de novo synthesis pathway via palmitate (24Suzuki J. Akahane K. Nakamura J. Naruse K. Kamiya H. Himeno T. Nakamura N. Shibata T. Kondo M. Nagasaki H. et al.Palmitate induces apoptosis in Schwann cells via both ceramide-dependent and independent pathways.Neuroscience. 2011; 176: 188-198Crossref PubMed Scopus (29) Google Scholar). Cer induces apoptosis via multiple mechanisms, such as through the inhibition of AKT-1 and activation of extrinsic and intrinsic apoptotic pathways (15Galadari S. Rahman A. Pallichankandy S. Galadari A. Thayyullathil F. Role of ceramide in diabetes mellitus: evidence and mechanisms.Lipids Health Dis. 2013; 12: 98Crossref PubMed Scopus (128) Google Scholar). These pathways converge on the cleavage of caspase-3 and result in DNA fragmentation, degradation of the cytoskeleton and nuclear proteins, and the formation of apoptotic bodies, including DNA fragments (e.g., DNA ladder) (25Pettus B.J. Chalfant C.E. Hannun Y.A. Ceramide in apoptosis: an overview and current perspectives.Biochim. Biophys. Acta. 2002; 1585: 114-125Crossref PubMed Scopus (674) Google Scholar). Apoptotic cell death is the potential driver for retinal neuron degeneration (e.g., photoreceptor cells, ganglion cells, and RPE cells), and this is what occurs in human retinitis pigmentosa, glaucoma, and AMD, respectively. In recent studies utilizing animal and cell culture models, Cer accumulation has been established as one of the underlying causes of retinal cell death (26German O.L. Miranda G.E. Abrahan C.E. Rotstein N.P. Ceramide is a mediator of apoptosis in retina photoreceptors.Invest. Ophthalmol. Vis. Sci. 2006; 47: 1658-1668Crossref PubMed Scopus (69) Google Scholar, 27Sanvicens N. Cotter T.G. Ceramide is the key mediator of oxidative stress-induced apoptosis in retinal photoreceptor cells.J. Neurochem. 2006; 98: 1432-1444Crossref PubMed Scopus (90) Google Scholar, 28Chen H. Chan A.Y. Stone D.U. Mandal N.A. Beyond the cherry-red spot: Ocular manifestations of sphingolipid-mediated neurodegenerative and inflammatory disorders.Surv. Ophthalmol. 2014; 59: 64-76Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Previously, using FTY720, a Cer synthase (CerS) inhibitor that blocks de novo light-induced Cer production (11Chen H. Tran J.T. Eckerd A. Huynh T.P. Elliott M.H. Brush R.S. Mandal N.A. Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration.J. Lipid Res. 2013; 54: 1616-1629Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 29Stiles M. Qi H. Sun E. Tan J. Porter H. Allegood J. Chalfant C.E. Yasumura D. Matthes M.T. LaVail M.M. et al.Sphingolipid profile alters in retinal dystrophic P23H–1 rats and systemic FTY720 can delay retinal degeneration.J. Lipid Res. 2016; 57: 818-831Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 30Berdyshev E.V. Gorshkova I. Skobeleva A. Bittman R. Lu X. Dudek S.M. Mirzapoiazova T. Garcia J.G. Natarajan V. FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells.J. Biol. Chem. 2009; 284: 5467-5477Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 31Lahiri S. Park H. Laviad E.L. Lu X. Bittman R. Futerman A.H. Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-dependent manner.J. Biol. Chem. 2009; 284: 16090-16098Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), we have shown that Cer plays a second-messenger role in the induction of retinal cell death, and that its inhibition can prevent and/or delay cell death (29Stiles M. Qi H. Sun E. Tan J. Porter H. Allegood J. Chalfant C.E. Yasumura D. Matthes M.T. LaVail M.M. et al.Sphingolipid profile alters in retinal dystrophic P23H–1 rats and systemic FTY720 can delay retinal degeneration.J. Lipid Res. 2016; 57: 818-831Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). Therefore, targeting Cer could be a potential strategy for developing neuroprotective therapies for retinal diseases. The enzyme group that hydrolyzes accumulated Cer into sphingosine (Sph) and releases free fatty acids is called ceramidase, also known as N-acylsphingosine amidohydrolase (ASAH). The lysosomal form of this enzyme is acid ceramidase, or ASAH1, and has very high expression in retinal and RPE cells [N. Mandal, unpublished observations; (6Kannan R. Jin M. Gamulescu M.A. Hinton D.R. Ceramide-induced apoptosis: role of catalase and hepatocyte growth factor.Free Radic. Biol. Med. 2004; 37: 166-175Crossref PubMed Scopus (58) Google Scholar)]. The lysosomal breakdown of Cer into Sph is the major source for intracellular Sph 1-phosphate (S1P) production, which has an opposing role to Cer and provides cytoprotection (32Olivera A. Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens.Nature. 1993; 365: 557-560Crossref PubMed Scopus (815) Google Scholar, 33Hannun Y.A. Obeid L.M. Principles of bioactive lipid signalling: lessons from sphingolipids.Nat. Rev. Mol. Cell Biol. 2008; 9: 139-150Crossref PubMed Scopus (2452) Google Scholar). We hypothesize that elevated ceramidase activity will reduce endogenous Cer levels, thereby protecting the cells from Cer-induced apoptosis. In this study, we show that Cer and hexosyl-Cer (Hex-Cer) levels increase in ARPE19 cells that are oxidatively stressed by hydrogen peroxide (H2O2), and that overexpression of lysosomal ASAH1 can reduce the levels of both of these bioactive lipids. ARPE19 cells are immortalized human RPE cells that maintain their native epithelial properties and are extensively used in eye research. This study demonstrates, for the first time, that the overexpression of ASAH1 could help to protect human retinal cells from oxidative stress-induced cell death. ARPE19 cells, a human RPE cell line, were kindly supplied by Leonard Hjelmeland at Univerity of California Davis. The cells were maintained in a DMEM (Invitrogen-Gibco, Tokyo, Japan) containing 10% FBS (Invitrogen-Gibco), antibiotics (Invitrogen-Gibco), and l-glutamine (Invitrogen-Gibco), as described previously (34Abe T. Tomita H. Ohashi T. Yamada K. Takeda Y. Akaishi K. Yoshida M. Sato M. Tamai M. Characterization of iris pigment epithelial cell for auto cell transplantation.Cell Transplant. 1999; 8: 501-510Crossref PubMed Scopus (29) Google Scholar). The cultures were maintained at 37°C in a humidified atmosphere containing 95% air:5% CO2." @default.
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• W2901787968 date "2019-01-01" @default.
• W2901787968 modified "2023-10-16" @default.
• W2901787968 title "Overexpression of acid ceramidase (ASAH1) protects retinal cells (ARPE19) from oxidative stress" @default.
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• W2901787968 doi "https://doi.org/10.1194/jlr.m082198" @default.
• W2901787968 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6314257" @default.
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