Age‐dependent variations in the drusen fluorescence on indocyanine green angiography

Chang, Andrew; Guyer, David R.; Orlock, Dennis A.; Yannuzzi, Lawrence A.

doi:10.1046/j.1442-9071.2003.00664.x

Cited by 16 publications

(8 citation statements)

References 29 publications

(52 reference statements)

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“…Anesthetized mice were injected intraperitoneally with 25% of fluorescein sodium (Fisher Scientific, Pittsburgh, PA, USA) at a dose of 50 µL per 25 g body weight 43 . Fundus photography and FA were performed in untouched, vehicle‐and griseofulvin‐injected animals 14 days post intravitreal injection using the Micron III retinal imaging system and StreamPix software (Montreal, Quebec, Canada) at various times following fluorescein injection.…”

Section: Methodsmentioning

confidence: 99%

Ferrochelatase regulates retinal neovascularization

2020

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Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen‐induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co‐localized with neovascular tufts. Partial loss‐of‐function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N‐methyl protoporphyrin had similar effects. Griseofulvin is an antifungal drug that inhibits FECH as an off‐target effect. Strikingly, intravitreal griseofulvin decreased both pathological tuft formation and areas of vasoobliteration compared to vehicle, suggesting potential as a FECH‐targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.

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Section: Methodsmentioning

confidence: 99%

Ferrochelatase regulates retinal neovascularization

2020

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“…Most came from older donors. Eyes chosen for use for protein identification by mass spectrometry included several 7 th decade donors and therefore had a younger mean age than the other groups [34].…”

Section: Methodsmentioning

confidence: 99%

Abundant Lipid and Protein Components of Drusen

et al. 2010

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BackgroundDrusen are extracellular lesions characteristic of aging and age-related maculopathy, a major retinal disease of the elderly. We determined the relative proportions of lipids and proteins in drusen capped with retinal pigment epithelium (RPE) and in RPE isolated from non-macular regions of 36 human retinas with grossly normal maculas obtained <6 hr after death.Methodology/Principal FindingsDruse pellets were examined by light and electron microscopy. Component proteins were extracted using novel methods for preserved tissues, separated, subjected to tryptic digestion and LC-MS(MS)2 analysis using an ion trap mass spectrometer, and identified with reference to databases. Lipid classes were separated using thin layer chromatography and quantified by densitometry. Major druse components were esterified cholesterol (EC), phosphatidylcholine (PC), and protein (37.5±13.7, 36.9±12.9, and 43.0±11.5 ng/druse, respectively). Lipid-containing particles (median diameter, 77 nm) occupied 37–44% of druse volume. Major proteins include vitronectin, complement component 9, apoE, and clusterin, previously seen in drusen, and ATP synthase subunit β, scavenger receptor B2, and retinol dehydrogenase 5, previously seen in RPE. Drusen and RPE had similar protein profiles, with higher intensities and greater variability in drusen. C8, part of the complement membrane attack complex, was localized in drusen by immunofluorescence.Conclusions/SignificanceAt least 40% of druse content is comprised by lipids dominated by EC and PC, 2 components that are potentially accounted for by just one pathway, the secretion of lipoproteins by RPE. Manipulating genes encoding apolipoprotein pathways would be a fruitful approach to producing drusen with high EC content in laboratory animals. Therapies that directly mitigate drusen should prepare for the substantial volume of neutral lipids. The catalog of major druse proteins is nearing completion.

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“…A recent study has defined distinct agedependent differences in the fluorescence pattern of drusen. This heterogeneity is suggested to be due to differential binding of extravasated fluorescence to the constituents and histological site of the drusen deposits (Chang et al 2003). …”

Section: Clinical Significance Of Drusenmentioning

confidence: 99%