Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration
- Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, Bethesda, MD 20892
- 1To whom correspondence should be addressed. e-mail: rodriguezi{at}nei.nih.gov
Abstract
This review will discuss the formation and potential implications of 7-ketocholesterol (7KCh) in the retina. 7KCh is a proinflammatory oxysterol known to be present in high amounts in oxidized LDL deposits associated with atheromatous plaques. 7KCh is generated in situ in these lipoprotein deposits where it can accumulate and reach very high concentrations. In normal primate retina, 7KCh has been found associated with lipoprotein deposits in the choriocapillaris, Bruch's membrane, and the retinal pigment epithelium (RPE). In photodamaged rats, 7KCh has been found in the neural retina in areas of high mitochondrial content, ganglion cells, photoreceptor inner segments and synapses, and the RPE. Intermediates found by LCMS indicate 7KCh is formed via a free radical-mediated mechanism catalyzed by iron. 7KCh seems to activate several kinase signaling pathways that work via nuclear factor κB and cause the induction of vascular endothelial growth factor, interleukin (IL)-6, and IL-8. There seems to be little evidence of 7KCh metabolism in the retina, although some form of efflux mechanism may be active. The chronic mode of formation and the potent inflammatory properties of 7KCh indicate it may be an “age-related” risk factor in aging diseases such as atherosclerosis, Alzheimer's, and age-related macular degeneration.
Footnotes
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- Abbreviations:
- ABCG1
- ATP binding cassette transporter G1
- AMD
- age-related macular degeneration
- apo
- apolipoprotein; CE, cholesteryl-ester
- CETP
- cholesterol-ester transfer protein
- CNV
- choroidal neovascularization
- 5, 6-epoxCh
- 5,6-epoxycholesterol
- ER
- endoplasmic reticulum
- ERK
- extracellular signal-regulated kinase
- 7HCh
- 7-αβ-hydroxycholesterol
- 24HCh
- 24(S)-hydroxycholesterol
- 25HCh
- 25-hydroxycholesterol
- 27HCh
- 27 or 26-hydroxycholesterol
- HPBCD
- hydroxypropyl-β-cyclodextrin
- 11β-HSD1
- 11β-hydroxysteroid dehydrogenase type 1
- IPM
- interphotoreceptor matrix
- 7KCh
- 7-ketocholesterol
- 7KChS
- ketocholesterol-3-sulfate
- LCAT
- lethicin-cholesterol acyltransferase
- LDLR
- LDL receptor
- IL
- interleukin
- LXR
- liver X receptor
- MAPK
- mitogen-activated protein kinase
- NFκB
- nuclear factor κB
- NOX-4
- NADPH oxidase 4
- 7OOCh
- 7-αβ-hydroperoxides
- OSBP
- oxysterol binding protein
- oxLDL
- oxidized LDL
- PLA2
- phospholipase A2
- RPE
- retinal pigment epithelium
- ROS
- reactive oxygen species
- SRBI and II
- scavenger receptors I and II
- UPR
- unfolded protein response
- 5,6-triol
- 5,6-dihydroxycholesterol
- VEGF
- vascular endothelial growth factor
- VSMC
- vascular smooth muscle cell
- Received December 11, 2009.
- Revision received June 18, 2010.
