Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

Stiles, Megan; Qi, Hui; Sun, Eleanor; Tan, Jeremy; Porter, Hunter; Allegood, Jeremy C.; Chalfant, Charles E.; Yasumura, Douglas; Matthes, Michael T.; LaVail, Matthew M.; Mandal, Nawajes A.

doi:10.1194/jlr.m063719

Cited by 33 publications

(37 citation statements)

References 71 publications

(96 reference statements)

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“…However, the mechanism by which reactive oxygen species induce RPE cell death is not fully understood. It is well-documented that oxidative stress (e.g., light, chemical, and physical) can induce excess Cer biosynthesis, and we, along with other laboratories, recently established that Cer accumulation causes retinal cell death (11,12,29,50). In this study, we found that ARPE19 cells overexpressing lysosomal ceramidase (ARPE19-ASAH1) were protected from H 2 O 2 -induced oxidative stress by reducing the levels of bioactive Cer and Hex-Cer and S1P levels.…”

Section: Discussionmentioning

confidence: 54%

“…This delicate balance, or rheostat, between these two molecules ultimately determines whether the cell undergoes apoptosis or proliferation (54). Consequently, targeting pathways that decrease Cer accumulation could be a promising therapeutic approach for treating or preventing RD, as we demonstrated in earlier studies (12,29). This is the first report that uses a genetic means to reduce excess cellular Cer by stably overexpressing the ceramidase enzyme in mammalian cells, ultimately preventing oxidative stressinduced cell death.…”

Section: Discussionmentioning

confidence: 75%

“…Sphingolipid extraction was performed according to previously established procedures (11,29,36). Briefly, samples were added to 1 ml of CH 3 OH and 0.5 ml of CHCl 3 , along with internal standards, into 13 × 100 mm borosilicate tubes with a Teflon-lined cap (60827-453; VWR).…”

Section: Quantitative Analysis Of Sphingolipidsmentioning

confidence: 99%

“…In recent studies utilizing animal and cell culture models, Cer accumulation has been established as one of the underlying causes of retinal cell death (26)(27)(28). Previously, using FTY720, a Cer synthase (CerS) inhibitor that blocks de novo light-induced Cer production (11,(29)(30)(31), 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 (29). Therefore, targeting Cer could be a potential strategy for developing neuroprotective therapies for retinal diseases.…”

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confidence: 99%

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Overexpression of acid ceramidase (ASAH1) protects retinal cells (ARPE19) from oxidative stress

Sugano

Edwards

Saha

et al. 2019

Journal of Lipid Research

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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 (1, 2). Dry-AMD often converts to wet-AMD, which is visionthreatening. Accumulation of undigested cellular debris (e.g., drusen), oxidative stress, and subsequent death and degeneration of RPE cells are important contributors to AMD pathology (3,4). 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 (5-7). 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 (8,9), while excessive amounts of Cer are often toxic and can result in cellular apoptosis (10). 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 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 Overexpression of acid ceramidase (ASAH1) protects retinal cells (ARPE19) from oxidative stress. J. Lipid Res. 2019. 60: 30-43. 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 (Supplementary key words N-acylsphingosine amidohydrolase 1 • ceramide • hexosyl-ceramide • lysosome, retinal pigment epithelium • retinal degeneration • age-related macular degeneration

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 75%

Section: Quantitative Analysis Of Sphingolipidsmentioning

confidence: 99%

mentioning

confidence: 99%

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Overexpression of acid ceramidase (ASAH1) protects retinal cells (ARPE19) from oxidative stress

Sugano

Edwards

Saha

et al. 2019

Journal of Lipid Research

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“…SPLs were analyzed in the Lipidomics Core at Virginia Commonwealth University, Richmond, VA, following previously published protocols (43)(44)(45)(46). Internal standards were purchased from Avanti Polar Lipids (Alabaster, AL).…”

Section: Extraction and Analysis Of Splsmentioning

confidence: 99%

Analysis of sphingolipids in human corneal fibroblasts from normal and keratoconus patients

Priyadarsini

Nicholas

et al. 2017

Journal of Lipid Research

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The pathophysiology of human keratoconus (KC), a bilateral progressive corneal disease leading to protrusion of the cornea, stromal thinning, and scarring, is not well-understood. In this study, we investigated a novel sphingolipid (SPL) signaling pathway through which KC may be regulated. Using human corneal fibroblasts (HCFs) and human KC cells (HKCs), we examined the SPL pathway modulation. Both cell types were stimulated by the three transforming growth factor (TGF)-β isoforms: TGF-β1 (T1), TGF-β2 (T2), and TGF-β3 (T3). All samples were analyzed using lipidomics and real-time PCR. Our data showed that HKCs have increased levels of signaling SPLs, ceramide (Cer), and sphingosine 1-phosphate (S1P). Treatment with T1 reversed the increase in Cer in HKCs and treatment with T3 reversed the increase in S1P. receptor mRNA levels were also significantly upregulated in HKCs, but were reduced to normal levels following T3 treatment. Furthermore, stimulation with Cer and S1P led to significant upregulation of fibrotic markers in HCFs, but not in HKCs. Additionally, stimulation with a Cer synthesis inhibitor (FTY720) led to significant downregulation of specific fibrotic markers in HKCs (TGF-β1, collagen type III, and α smooth muscle actin) without an effect on healthy HCFs, suggesting a causative role of Cer and S1P in fibrogenesis. Overall, this study suggests an association of the SPL signaling pathway in KC disease and its relation with the TGF-β pathway.

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Inflammatory Ocular Diseases and Sphingolipid Signaling

Grambergs

Mondal

Mandal

2019

Bioactive Ceramides in Health and Disease

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Sphingolipid profile alters in retinal dystrophic P23H-1 rats and systemic FTY720 can delay retinal degeneration

Cited by 33 publications

References 71 publications

Overexpression of acid ceramidase (ASAH1) protects retinal cells (ARPE19) from oxidative stress

Overexpression of acid ceramidase (ASAH1) protects retinal cells (ARPE19) from oxidative stress

Analysis of sphingolipids in human corneal fibroblasts from normal and keratoconus patients

Inflammatory Ocular Diseases and Sphingolipid Signaling

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