Apoptosis in Surgically Excised Choroidal Neovascular Membranes in Age-Related Macular Degeneration

Hinton, David R.; He, Shikun; Lopez, Pedro F.

doi:10.1001/archopht.116.2.203

Cited by 92 publications

(67 citation statements)

References 38 publications

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“…Very recently, RPE cell apoptosis was shown to be the suicide mechanism involved in human agerelated macular degeneration and in in vivo and in vitro experimental models of RPE cell death (Hinton et al, 1998). We found that RPE cell apoptosis due to serum deprivation was mediated by the activation of a caspase 3-like pathway and not by a caspase 1-like pathway.…”

Section: Discussionmentioning

confidence: 71%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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Retinal pigmented epithelial (RPE) cells are of central importance in the maintenance of neural retinal function. Changes in the RPE cells associated with repair activities have been described as metaplasia, while RPE cell apoptosis is responsible for the development of a variety of retinal degenerations. We investigated the regulation of the anti-apoptotic properties of the ®broblast growth factors (FGF) 2 in serum-free cultures of RPE cells. In the absence of serum, con¯uent stationary RPE cells died by apoptosis via a caspase 3-dependent pathway. The addition of FGF2 greatly reduced apoptosis over a 7-day culture period. We demonstrated the involvement of an autocrine loop involving endogenous FGF1 in the mechanisms that govern FGF2-induced resistance to apoptosis by showing: (1) higher levels of apoptosis in cells treated with antisense FGF1 oligonucleotide or after neutralization of excreted FGF1; (2) the long-term activation of FGFR1 and of ERK2, (3) the inhibition of FGFR1 and ERK2 activation and an increase in apoptosis if excreted FGF1 was neutralized. FGF2 also increased the de novo synthesis and the production of Bcl-xl before the onset of apoptosis. Both inhibition of ERK2 activation, which decreased Bcl-xl synthesis, and downregulation of Bcl-x by antisense oligonucleotide treatment inhibited the survival-promoting activity of FGF2. Thus, FGF2-induced cell survival is a progressive adaptive phenomenon involving ERK2 activation by excreted FGF1 and ERK2-dependent Bcl-x production.

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Section: Discussionmentioning

confidence: 71%

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Bryckaert

Guillonneau²,

Hecquet³

et al. 1999

Oncogene

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“…Again, the local latency results showed no significant differences (F (2,47) ¼ 0.03, P ¼ 0.87) between the two measurements, suggesting that it is a robust and relatively stable measure. We found an increased mean amplitude by about 28% (F (2,47) ¼ 24.6, Po0.01), which may be due to stray light influence, which is thought to be greater in an older population according to Hood et al 27 The scatter of increased lens opacities 1 year later together with the dilated pupil (larger than 8 mm) probably caused such an amplitude increase.…”

Section: Repeatability Of Rod-mediated Mferg Datamentioning

confidence: 84%

“…Recent human and animal studies in ARM eyes have found a loss of photoreceptors, RPE cells, and inner nuclear layer cells by apoptosis, preferentially affecting the rods. [44][45][46][47] Curcio et al 3,4 hypothesized a vitamin A deficiency and therefore a retinoid deficiency, resulting from a reduced translocation of the retinoids from the blood across Bruch's membrane due to the accumulated cell debris between Bruch's membrane and the RPE. Another reason for preferential rod rather than cone vulnerability might be their larger oxygen requirements; 48 a reduced choroidal blood flow has been demonstrated in ARM.…”

Section: Discussionmentioning

confidence: 99%

Cone- and rod-mediated multifocal electroretinogram in early age-related maculopathy

Feigl

Brown

Lovie‐Kitchin

et al. 2004

Eye

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Purpose To investigate the cone-and rodmediated multifocal electroretinograms (mfERG) in early age-related maculopathy (early ARM). Methods and subjects We investigated the cone-and rod-mediated mfERG in 17 eyes of 17 subjects with early ARM and 16 eyes of 16 age-matched control subjects with normal fundi. All subjects had a visual acuity of 6/12 or better. We divided the ARM subjects into two groups based on drusen size and retinal pigment epithelium abnormalitiesFa less advanced (ARM1) and a more advanced (ARM2) group. The mfERG data were compared to templates derived from the control group. We analysed the mfERG results for the central and peripheral fields (CP method) and the superior and inferior fields (SI method). Results While the mean cone results showed no statistically significant difference between the groups, the rods showed significantly delayed responses in the ARM1 group for the CP and the SI methods, but not in the ARM2 group, although there was a trend of longer latencies compared to the control group. Conclusion Our results show a functional impairment of the rods in early ARM subjects. As there is histopathological evidence showing earlier rod than cone impairment in early ARM, following the rod function with the mfERG might be helpful in diagnosis or for monitoring the progression of early ARM.

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“…The reduction of apoptosis mediated by endogenous FGF1 requires FGF1 release in non-proliferating RPE cells RPE cell apoptosis has been shown to be the suicide mechanism involved in human age-related macular degeneration and in in vitro and in vivo models of RPE cells (Hinton et al, 1998). The widespread presence of FGFs and FGFRs in non-dividing cells suggests that FGF signalling may be involved in cell survival without inducing cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells

et al. 2000

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Fibroblast growth factor 1 (FGF1) induces proliferation and dierentiation in a wide variety of cells of mesodermal and neuroectodermal origin. FGF1 has nò classical' signal sequence to direct its secretion, and there has been considerable debate concerning FGF1 secretion and its role in the biological activities of FGF1. We investigated the eects of FGF1 secretion and the signalling induced by signal peptide (SP)-containing FGF1 and SP-less FGF1, on the proliferation and the apoptosis in retinal pigmented epithelial (RPE) cells. Primary RPE cell cultures were transfected with FGF1 (FGF1 cells) and SP-FGF1 (SP-FGF1 cells) cDNAs. SP-FGF1 cells secreted large amount of FGF1 and actively proliferated, whereas FGF1 and control cells did not. Secreted FGF1 induced short-term activation of both FGFR1 and ERK2, which were required for cell proliferation. In contrast, SP-FGF1 cells stopped secreting FGF1 and died rapidly, if cultured in the absence of serum. Surprisingly, FGF1 cells, but not control cells, secreted FGF1 and were resistant to apoptosis induced by serum depletion. Secreted FGF1 induced long-term activation of FGFR1 and ERK2, which was necessary to induce a constant and high level of Bcl-x production, and to induce cell survival in FGF1 cells. Downregulation of ERK2 and Bcl-x increased apoptosis. Thus, the proliferation and survival activities of FGF1 depend on the secretion of FGF1 which is determined by the cell culture conditions. Cell proliferation was SP-dependent, whereas cell survival was not. The signal peptide controls the level and duration, whispering or shouting', of ERK2 activation cells which determines FGF1 biological function and may have important implications for anti-degenerative and antiproliferative treatments. Oncogene (2000) 19, 4917 ± 4929.

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Apoptosis in Surgically Excised Choroidal Neovascular Membranes in Age-Related Macular Degeneration

Cited by 92 publications

References 38 publications

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Both FGF1 and Bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2

Cone- and rod-mediated multifocal electroretinogram in early age-related maculopathy

Regulation of proliferation-survival decisions is controlled by FGF1 secretion in retinal pigmented epithelial cells

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