Impairment with various antioxidants of the loss of mitochondrial transmembrane potential and of the cytosolic release of cytochrome c occuring during 7-ketocholesterol-induced apoptosis

Lizard, Gérard; Miguet, Carole; Bessède, Ginette; Monier, Serge; Gueldry, Serge; Néel, Dominique; Gambert, Philippe

doi:10.1016/s0891-5849(00)00163-5

Cited by 129 publications

(83 citation statements)

References 50 publications

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“…Recent studies have suggested that the cell damage induced by 7-Kchol, which can be prevented by antioxidant agents such as glutathione, N-acetylcysteine and vitamin E may be due to ROS production (28,29). Here we show that 7-Kchol-treated SMCs undergo apoptosis characterized by phosphatidylserine externalization, loss of mitochondrial transmembrane potential, modification of both antiapoptotic Bcl-2 and proapoptotic Bax expression, and caspase activation.…”

Section: Discussionsupporting

confidence: 47%

NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

Pédruzzi

Guichard

Ollivier

et al. 2004

Molecular and Cellular Biology

386

318

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The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase homologue. This effect was highlighted by silencing Nox-4 expression with a specific small interfering RNA, which significantly reduced the 7-Kchol-induced production of ROS and abolished apoptotic events. Furthermore, the 7-Kchol activating pathway included an early triggering of endoplasmic reticulum stress, as assessed by transient intracellular Ca 2؉ oscillations, and the induction of the expression of the cell death effector CHOP and of GRP78/Bip chaperone via the activation of IRE-1, all hallmarks of the unfolded protein response (UPR). We also showed that 7-Kchol activated the IRE-1/Jun-NH 2 -terminal kinase (JNK)/AP-1 signaling pathway to promote Nox-4 expression. Silencing of IRE-1 and JNK inhibition downregulated Nox-4 expression and subsequently prevented the UPR-dependent cell death induced by 7-Kchol. These findings demonstrate that Nox-4 plays a key role in 7-Kchol-induced SMC death, which is consistent with the hypothesis that Nox-4/oxysterols are involved in the pathogenesis of atherosclerosis.Atherosclerosis is a slow degenerative process and is the underlying cause of heart attacks, strokes, and peripheral artery diseases in humans. This complex disorder is characterized by a remodeling of the arterial wall, leading to the formation of an atherosclerotic plaque. Plaque formation is induced by the accumulation, at the subendothelial level, of oxidized low-density lipoproteins (LDLs) and subsequently of some of their lipid constituents (oxysterols, oxidized fatty acids, aldehydes, and lysophospholipids) and fibrous elements.To date, a number of studies have shown that oxysterols constitute an important family of oxygenated derivatives of cholesterol that exert potent biological effects in the pathogenesis of atherosclerosis (for a review, see references 6 and 9). Among the oxysterols that have been identified, those oxidized at the C7 position, such as 7-ketocholesterol (7-Kchol), are the ones most frequently detected at high levels in atherosclerotic plaques (9) and in the plasma of patients with high cardiovascular risk factors (55). 7-Kchol exerts deleterious effects on vascular smooth muscle cells (SMCs), including the stimulation of reactive oxygen species (ROS) production (28) and the induction of apoptosis (30,34,42), two major events involved in atherogenesis. The oxidation of macromolecules (proteins, lipids, and DNA) and apoptosis induce the progression of atherosclerosis. Thus, the death of vascular SMCs and monocyte-derived foam cells has been shown to modulate the cellularity of...

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Section: Discussionsupporting

confidence: 47%

NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

Pédruzzi

Guichard

Ollivier

et al. 2004

Molecular and Cellular Biology

386

318

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“…Interestingly, some antioxidants [apigenin, astaxanthin, carotene, folate, glutathione, lycopene, N-acetylcysteine, vitamin E (α-tocopherol)] have been described as preventing oxysterol-induced cell death (27,41,46). Oxysterol mixtures, in atheroma-relevant proportions, also display pro-oxidative activities.…”

Section: Oxysterols: Potent Pro-oxidative Moleculesmentioning

confidence: 99%

“…It has also been suggested, with cytotoxic oxysterols (15) and cationic amphiphilic drugs (29), that the rupture of the acidic compartments containing multilamellar structures might favor the release of some proteolytic enzymes into the cytoplasm, which could subsequently contribute to activating certain apoptotic pathways. Moreover, since vitamin E and caspase inhibitors (z-VAD-fmk: broad-spectrum caspase inhibitor; z-VDVADfmk: caspase-2 inhibitor) can counteract phospholipidosis, as well as certain apoptotic-associated events (caspase activation, lysosomal degradation) (30,41), it is tempting to speculate that phospholipidosis and cell death may have common signaling pathways. Therefore, the ability of cytotoxic oxysterols to activate intracellular lipid accumulation (mainly polar lipids) favors the hypothesis that the balance between these oxysterols and vitamin E might play key roles in the lipid profile of atherosclerotic lesions (Figure 3), Figure 3.…”

Section: Cytotoxic Oxysterols: Powerful Inducers Of Phospholipidosismentioning

confidence: 99%

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

Véjux

Malvitte

Lizard³

2008

Braz J Med Biol Res

148

132

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“…2) is unlikely to be physiologically relevant. In vivo the delivery of 7kCh is mainly via oxidized lipid particles like LDL, and the cytotoxicity of 7kCh is due to loss of mitochondrial transmembrane potential (Lizard et al, 1999). Conversely, the fact that CYP27A1 is a mitochondrial enzyme known to metabolize 7kCh to 27OH7kCh (Jessup and Brown, 2005) and that 7kCh can affect mitochondrial function, suggests that the protection by 27OH7kCh may be of physiological importance.…”

Section: Introductionmentioning

confidence: 99%

Expression and localization of sterol 27-hydroxylase (CYP27A1) in monkey retina

Lee

Fuda

Javitt

et al. 2006

Experimental Eye Research

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Sterol 27-hydroxylase (CYP27A1) is a mitochondrial P-450 enzyme with broad substrate specificity for C27 sterols including 7-ketocholesterol (7kCh). CYP27A1 is widely expressed in human tissues but has not been previously demonstrated in the retina. In this study, we examined the expression and localization of CYP27A1 in the monkey retina where it localized mainly to the photoreceptor inner segments. CYP27A1 was also observed in Müller cells with faint immuno staining detected in the RPE and choriocapillaris. We also determined that the 27-hydroxylation of 7-ketocholesterol (27OH7kCh) rendered it non-toxic to cultured RPE cells. Moreover, the 27OH7kCh when mixed with 7-ketocholesterol significantly reduced the toxicity of 7-ketocholesterol. These data, when taken in context of the known functions of CYP27A1 imply that expression in the retina serves to modify the biological activity of oxidized sterols that are either transported or generated locally by photooxidation. Published by Elsevier Ltd. Keywords cholesterol efflux; macula; 7-ketocholesterol; ARPE19; photoreceptors The sterol 27-hydroxylase (CYP27A1:P450c27, Andersson et al., 1989) is a mitochondrial enzyme that performs multiple functions (Javitt, 2002, review): it is known to catalyze bile acid hydroxylations (Russell, 2003, review) and to activate vitamin D (Usui et al., 1990); furthermore, the formation of 27-hydroxycholesterol (27OHCh) by CYP27A1 has been demonstrated to stimulate cholesterol efflux in cultured cells (Escher et al., 2003). CYP27A1 is deficient in individual with the rare disease cerebrotendinous xanthomatosis (CTX) . CTX patients suffer from progressive neurological impairment as well as accelerated atherosclerosis and cataracts (Moghadasian, 2004, review).CYP27A1 readily hydroxylates the oxysterol 7-ketocholesterol (7kCh) to 27-hydroxy-7-ketocholesterol (27OH7kCh) (Brown et al., 2000), which is highly toxic to a variety of cells (Lyons and Brown, 1999) including RPE cells and is the main cholesterol oxide in oxidized low density lipoprotein (Brown et al., 1996) (Brown and Jessup, 1999).The rationale for this study is threefold: (1) CYP27A1 is known to be involved in the cholesterol efflux pathway (Escher et al., 2003), (2) CYP27A1 is known to be involved in the metabolism of 7kCh (Brown et al., 2000;Lyons and Brown, 2001;Jessup and Brown, 2005) and (3) despite the extensive knowledge of cholesterol hydroxylation in the brain (Björkem and Meaney, 2004; Diestschy and Turley, 2004, reviews), there are no published reports concerning CYP27A1 (or other sterol hydroxylases) in the retina. The retina is known to perform de novo synthesis (Fliesler et al., 1993) as well as cholesterol uptake from circulating blood lipoproteins (Elner, 2002;Gordiyenko et al., 2004). However, little is known about the cholesterol efflux or how the retina maintains cholesterol homeostasis. CYP27A1 may be involved in cholesterol efflux by forming 27OHCh which can change the lipid composition of the plasma membrane and/or can alter gene expression by ...

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Impairment with various antioxidants of the loss of mitochondrial transmembrane potential and of the cytosolic release of cytochrome c occuring during 7-ketocholesterol-induced apoptosis

Cited by 129 publications

References 50 publications

NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

Expression and localization of sterol 27-hydroxylase (CYP27A1) in monkey retina

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