Cellular toxicity of oxycholesterols

Wielkoszyński, Tomasz; Gawron, Katarzyna; Strzelczyk, Joanna Katarzyna; Bodzek, Piotr; Zalewska‐Ziob, Marzena; Trapp, Gizela; Srebniak, Malgorzata I.; Wiczkowski, Andrzej

doi:10.1002/bies.20383

Cited by 25 publications

(17 citation statements)

References 92 publications

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“…Among the oxysterols considered (7KC,5 ,5 ,, and in agreement with previous investigations Wielkoszynski et al 2006), cytotoxic activities including increased permeability to PI, and morphological nuclear changes (cells with swollen nuclei considered as oncotic cells; cells with condensed and/or fragmented nuclei characteristic of apoptotic cells) (Majno and Joris 1995;Fink and Cookson 2005) were only observed with 7-KC, 7 -OH, and 5 ,6 -epoxide. Moreover, as myelin Wgures were only detected with these cytotoxic oxysterols, and as they were not found in treatments with the potent inducers of apoptosis or autophagy studied daunorubicin,tunicamycin,rapamycin), nor with cytosine -D-arabinofuranoside, vinblastine, cycloheximide, or staurosporine (MiguetAlfonsi et al 2002), our observations reinforce the hypothesis that multilamellar structures might constitute suitable markers of oxysterol-induced cell death.…”

Section: Discussionsupporting

confidence: 89%

Cytotoxic oxysterols induce caspase-independent myelin figure formation and caspase-dependent polar lipid accumulation

Véjux

Kahn

Ménétrier

et al. 2007

Histochem Cell Biol

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Oxysterols, mainly those oxidized at the C7 position, induce a complex mode of cell death exhibiting some characteristics of apoptosis associated with a rapid induction of lipid rich multilamellar cytoplasmic structures (myelin figures) observed in various pathologies including atherosclerosis. The aim of this study was to determine the relationships between myelin figure formation, cell death, and lipid accumulation in various cell lines (U937, THP-1, MCF-7 [caspase-3 deficient], A7R5) treated either with oxysterols (7-ketocholesterol [7KC], 7beta-hydroxycholesterol, cholesterol-5alpha,6alpha-epoxide, cholesterol-5beta,6beta-epoxide, 25-hydroxycholesterol) or cytotoxic drugs (etoposide, daunorubicin, tunicamycin, rapamycin). Cell death was assessed by the measurement of cellular permeability with propidium iodide, characterization of the morphological aspect of the nuclei with Hoechst 33342, and identification of myelin figures by transmission electron microscopy. Nile Red staining (distinguishing neutral and polar lipids) was used to identify lipid content by flow cytometry and spectral imaging microscopy. Whatever the cells considered, myelin figures were only observed with cytotoxic oxysterols (7KC, 7beta-hydroxycholesterol, cholesterol-5beta, 6beta-epoxide), and their formation was not inhibited by the broad spectrum caspase inhibitor z-VAD-fmk. When U937 cells were treated with oxysterols or cytotoxic drugs, polar lipid accumulation was mainly observed with 7KC and 7beta-hydroxycholesterol. The highest polar lipid accumulation, which was triggered by 7KC, was counteracted by z-VAD-fmk. These findings demonstrate that myelin figure formation is a caspase-independent event closely linked with the cytotoxicity of oxysterols, and they highlight a relationship between caspase activity and polar lipid accumulation.

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Section: Discussionsupporting

confidence: 89%

Cytotoxic oxysterols induce caspase-independent myelin figure formation and caspase-dependent polar lipid accumulation

Véjux

Kahn

Ménétrier

et al. 2007

Histochem Cell Biol

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“…Since it is well established that some oxysterols have detrimental biological activities (induction of cell death, pro-oxidative and pro-inflammatory activities) (Björkhem and Diczfaluzsy, 2002;Carpenter, 2002;Meynier et al, 2005;Van Reyk et al, 2006;Wielkoszynski et al, 2006), they can therefore contribute to the initiation and development of important diseases.…”

Section: Physiological Activities and Physiopathological Relevance Ofmentioning

confidence: 99%

“…Since atherosclerosis is characterized early at the subendothelial level by an intracellular accumulation of lipids in macrophages and smooth muscle cells (Berliner and Heinecke, 1996), and given that these cells can transform into foam cells (Bobryshev, 2006), which are lipid-laden cells of the first step of atherosclerosis (Stary et al, 1995), it is important to specify the role played by some oxysterols in intracellular lipid accumulation, especially with oxysterols present at high levels in atherosclerotic plaques, which can induce cytotoxic effects from 7-ketocholesterol and 7b-hydroxycholesterol, for example (Brown and Jessup, 1999;Wielkoszynski et al, 2006). Death of macrophage foam cells leads to the development of the lipid core of advanced atherosclerotic lesions while the death of smooth muscle cells thins the fibrous cap.…”

Section: Cytotoxic Oxysterols and Induction Of Phospholipidosismentioning

confidence: 99%

Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis

Véjux

Lizard

2009

Molecular Aspects of Medicine

250

205

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“…This occurs readily in lipoprotein deposits and atherosclerotic plaques. The enzymatic pathways can form both B-ring and side-chain hydroxylated oxysterols depending on the enzyme and the tissue ( 5,7,(30)(31)(32) ( Fig. 1B ).…”

Section: Cholesterol Oxidation In the Retinamentioning

confidence: 99%

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

Rodríguez

Larráyoz

2010

Journal of Lipid Research

121

115

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Journal of Lipid Research Volume 51, 20102847 their actions affect the retina and the retinal pigment epithelium (RPE) ( 8-10 ). One particular oxysterol, 7-ketocholesterol (7KCh), has been found more abundantly than other oxysterols in the retina ( 9, 10 ). This oxysterol is known to have potent pharmacological properties that lead to infl ammation and cell death in a variety of cell types ( 1-10 ). This review will focus on what is known about this molecule and the potential implications of its presence in the retina. The retina is a light-capturing tissue that contains at least 5 cell classes and more than 50 different cell types, each performing unique functions that ultimately provide the visual centers in the brain the information to achieve image formation and visual perception. The retina faces a unique photooxidative environment that generates challenges not encountered by other neurological tissues or organs. Phototransduction requires the retina to have a high metabolic rate ( 11 ) and multiple and complex membrane structures ( 12 ). The photoreceptor outer segments are enriched in the highly photosensitive docosahexaenoic acid and other Abstract This review will discuss the formation and potential implications of 7-ketocholesterol (7KCh) in the retina. 7KCh is a proinfl ammatory 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 B 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 effl ux mechanism may be active. The chronic mode of formation and the potent infl ammatory 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. -Rodríguez, I. R., and I. M. Larrayoz. Cholesterol oxidation in the retina: implications of 7-KCh formation in chronic infl ammation and age-related macular degeneration. J. Lipid Res . 2010. 51: 2847-2862. Supplementary key words 7-ketocholesterol • cytokines • oxysterolsIn the past year, numerous reviews have been published that extensively discuss the multiple functions of oxysterols and their complex relationships to diseases ( 1-7 ). However, the formation and function of oxysterols in the retina has not been well studied. Emerging studies are...

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Cellular toxicity of oxycholesterols

Cited by 25 publications

References 92 publications

Cytotoxic oxysterols induce caspase-independent myelin figure formation and caspase-dependent polar lipid accumulation

Cytotoxic oxysterols induce caspase-independent myelin figure formation and caspase-dependent polar lipid accumulation

Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

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