FAS-Mediated Apoptosis and Its Relation to Intrinsic Pathway Activation in an Experimental Model of Retinal Detachment

Zacks, David N.; Zheng, Qi; Han, Ying; Bakhru, Rita; Miller, Joan W.

doi:10.1167/iovs.04-0598

Cited by 92 publications

(107 citation statements)

References 15 publications

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“…S7 C and D), suggesting that TNF-α may contribute to the induction of apoptosis and programmed necrosis. In addition to TNF-α, Fas-L/Fas pathway is known to be activated and mediate photoreceptor death after retinal detachment (19,42), and may cooperate with TNF-α to activate RIP kinases and promote programmed necrosis in addition to apoptosis. Thus, RIP kinases act as common intermediaries for various upstream death signals and their blockade in addition to caspases is likely necessary for effective neuroprotection (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…During death domain receptor-induced apoptosis, RIP1 is cleaved and inactivated by caspase-8, the process of which is prevented by caspase inhibition (13). It has been unclear how RIP1 kinase mediates programmed necrosis, but recent studies revealed that the expression of RIP3 and the RIP1-RIP3 binding through the RIP homotypic interaction motif is a prerequisite for RIP1 kinase activation, leading to reactive oxygen species (ROS) production and necrotic cell death (14-16).In a rodent model of retinal detachment, we have shown that TNF-α expression levels increase substantially (17) and that caspases are activated after retinal detachment (18,19). However, caspase inhibition by Z-VAD fails to prevent the retinal detachment-induced photoreceptor death (20).…”

mentioning

confidence: 99%

“…In a rodent model of retinal detachment, we have shown that TNF-α expression levels increase substantially (17) and that caspases are activated after retinal detachment (18,19). However, caspase inhibition by Z-VAD fails to prevent the retinal detachment-induced photoreceptor death (20).…”

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Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis

Trichonas

Murakami

Thanos

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspasedependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders.degenerations | necroptosis P hotoreceptor death and subsequent visual decline occurs when the photoreceptors are separated from the underlying retinal pigment epithelium. Physical separation of photoreceptors is seen in various retinal disorders, including age-related macular degeneration (1), diabetic retinopathy (2), as well as rhegmatogenous (i.e., caused by a break in the retina) retinal detachment (3, 4). Although surgery is carried out to reattach the retina, only two fifths of patients with rhegmatogenous retinal detachment involving the macula, a region essential for central vision, recover 20/40 or better vision because of photoreceptor death (4, 5). Thus, identification of the mechanisms that underlie photoreceptor death is critical to developing new treatment strategies for these diseases.Apoptosis and necrosis are two major cell death modalities (6). Apoptosis is a highly regulated process involving the caspase family of cysteine proteases. In contrast, necrosis has been considered a passive, unregulated form of cell death; however, recent evidence indicates that some necrosis can be induced by regulated signal transduction pathways such as those mediated by receptor interacting protein (RIP) kinases, especially in conditions in which caspases are inhibited or cannot be activated efficiently (7,8). Stimulation of the Fas and TNFR family of death domain receptors is known to mediate apoptosis in most cell types through the activation of the extrinsic caspase pathway. In addition, in certain cells deficient for caspase-8 or treated with the pan-caspa...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis

Trichonas

Murakami

Thanos

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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279

276

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“…Earlier studies mainly focused on the mitochondrion-mediated pathway; the existence of mitochondrion-mediated pathway has been confirmed in the apoptosis of photoreceptors whereby the inhibition of key factors in above pathway prevented the photoreceptors from apoptosis. [8][9][10] However, the inhibitors can only partly rescue photoreceptors, suggesting the existence of other pathways for the apoptosis process after RD.…”

Section: Introductionmentioning

confidence: 99%

Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication

Liu

Qian

Wang

et al. 2009

Eye

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Purpose To investigate the expression of endoplasmic reticulum (ER) stress-related genes, glucose-regulated protein 78 (GRP78) and growth arrest DNA damage-inducible gene 153 (GADD153)/CPEBP homologous protein (CHOP), in rat retinal detachment (RD) model. Materials and methods At various time points after RD, the apoptosis of retinal cells was detected by TdT-mediated fluorescein-16-dUTP nick-end labelling (TUNEL) assay; GRP78 and GADD153 mRNA levels were detected by reverse transcription (RT)-PCR; proteins were detected by western blotting analysis; protein distributions in the retinal cells were observed by immunofluorescence using laser-scanning confocal microscope. Results After RD, the apoptosis was peaked on 2-4 d and then dropped down. The GRP78 mRNA and GADD153 mRNA levels in RD groups on 0.5, 1, 2, and 4 d were all significantly higher than those in the control group (Po0.05). The expression of GRP78 mRNA peaked on 1-2 d after RD. Expression of GRP78 protein was significantly higher than that in the normal control group on 0.5, 1, 2, 4, 8, 16, and 32 d after RD (Po0.05). The expression of GRP78 protein was observed in all the layers of retina in the RD groups, and peaked on 8, 16, and 32 d. The expression of GADD153 protein, mostly in photoreceptor layers, was significantly higher than that in the control group on 0.5, 1, 2, and 4 d after RD (Po0.05). Conclusions ER stress-related markers, GRP78 and GADD153, are elevated after RD.The elevation of GADD153 is in parallel with the post-RD apoptosis of retinal cells, suggesting that ER stress-mediated death is likely to be activated after RD and involved in post-RD vision loss.

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“…31,32 This study showed that exogenous EPO after RD significantly reduced the number of TUNEL-positive cells, indicating that EPO partially inhibited apoptosis. Caspase-3 is the final executor of apoptosis and is also involved in photoreceptor cell apoptosis after RD.…”

Section: Eyementioning

confidence: 78%

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

Xie

Chen

et al. 2011

Eye

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Purpose To elucidate the safety and efficacy of exogenous erythropoietin (EPO) for the protection of photoreceptor cells in a rat model of retinal detachment (RD). Methods Recombinant rat EPO (400 ng) was injected into the vitreous cavity of normal rats to observe the eye manifestations. Retinal function was assessed by flash electroretinograms. Histopathological examination of retinal tissue was performed at 14 days and 2 months after injection, respectively. To investigate the inhibitory effect of EPO on photoreceptor cell apoptosis in RD rats, 100, 200, or 400 ng EPO was injected into the vitreous cavity immediately after RD model establishment. Apoptosis of photoreceptor cells was determined at 3 days after injection. Caspase-3 activation was measured by western blot analysis and immunofluorescence, respectively, and the level of Bcl-X L expression was analyzed by western blot. Results Intravitreal injection of EPO 400 ng into normal rats had no significant impact on retinal function, morphology, or structure. Apoptosis of retinal photoreceptor cells apparently increased after RD and was significantly reduced following EPO treatment. The thickness of the outer nuclear layer in the RD þ 400 ng group was significantly thicker than that in other experimental RD groups both at 14 days and at 2 months after RD (Po0.05). Western blot and immunofluorescence analyses showed decreased caspase-3 activation and increased Bcl-X L expression following EPO treatment. Conclusion Intravitreal injection of EPO 400 ng is safe, and EPO may suppress caspase-3 activation and enhance Bcl-X L expression, resulting in inhibition of apoptosis and protection of photoreceptor cells.

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FAS-Mediated Apoptosis and Its Relation to Intrinsic Pathway Activation in an Experimental Model of Retinal Detachment

Abstract: The FAS-mediated apoptosis pathway becomes activated and transcriptionally upregulated after retinal detachment. The peak of FAS activation precedes that of the intrinsic pathway, and inhibition of FAS activation can decrease caspase-9 activity.

Cited by 92 publications

References 15 publications

Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis

Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis

Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication

Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment

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