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Abstract

Oxidative stress occurs in chronic renal failure patients undergoing hemodialysis (HD). The objective of our study was to measure oxidation products of cholesterols, so-called oxysterols, in the serum of HD patients in comparison to healthy control persons. In 42 HD patients, plasma oxysterols were measured before and after HD. The values were compared with those in 40 healthy controls. The following cholesterol derivatives were analyzed: dienes, 7beta-OH, beta-epoxy, alpha-epoxy, 20alpha-OH, alpha-triol, and 7-keto cholesterol. In HD patients, serum levels of oxysterols are increased in comparison to controls. The highest values were measured for beta-epoxy cholesterol and for 20alpha-OH cholesterol. During HD oxysterol concentrations increased, obviously by water removal and concentration of nondialyzable compounds. Due to oxidative stress which is known as a typical sign of chronic renal failure the plasma concentrations of oxysterols are also significantly increased in comparison to healthy controls. This underlines the data on accelerated lipid peroxidation in end-stage renal disease (ESRD) patients. Accumulated oxysterols which are accused of exerting atherosclerosis-stimulating effects, which can contribute to the increased cardiovascular risk of ESRD patients, could either induce atherosclerosis via signaling or chronic effects. Direct chemical reactions stimulating plaque formation can be excluded because of the low levels of oxysterols. The share of oxysterols within the total cholesterol ranges from 4 to 15 per thousand. Copyright 2005 S. Karger AG, Basel.

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NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells.

J-L Marié, Cécile Guichard, Fathi Driss … (2004)

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.

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Oxysterols and atherosclerosis

Andrew Brown, Wendy Jessup (1999)

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7-ketocholesterol induces protein ubiquitination, myelin figure formation, and light chain 3 processing in vascular smooth muscle cells.

Wim Martinet, James G. Herman, R Agusti … (2004)

Oxysterols such as 7-ketocholesterol (7-KC) are important mediators of cell death in atherosclerosis. Therefore, in vitro studies of human smooth muscle cell (SMC) death in response to 7-KC were undertaken to investigate the potential mechanisms. Human aortic SMCs treated with 7-KC showed enhanced immunoreactivity for the oxidative stress marker 4-hydroxy-2-nonenal and upregulated several stress genes (70-kDa heat shock protein 1, heme oxygenase 1, and growth arrest and DNA damage-inducible protein 153) at the mRNA but not at the protein level. 7-KC-treated SMCs rapidly underwent cell death as determined by neutral red, counting of adherent cells, and depolarization of the mitochondrial inner membrane. Cell death was associated with upregulation of ubiquitin mRNA and ubiquitination of cellular proteins. Inhibition of the proteasome by lactacystin potentiated considerably the toxicity of 7-KC. Transmission electron microscopy revealed formation of myelin figures, extensive vacuolization, and depletion of organelles. Formation of autophagosomes was suggested by labeling cells with LysoTracker and monitoring processing of microtubule-associated protein 1 light chain 3 (LC3). Analogous to our in vitro studies, human atherosclerotic plaques showed signs of ubiquitination in SMCs. 7-KC activates the ubiquitin-proteasome system and induces a complex mode of cell death associated with myelin figure formation and processing of LC3 evocating autophagic processes.

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PubMed ID:: 16534225

DOI:: 10.1159/000091133

ScienceOpen disciplines: Chemistry

Keywords: Aged,Cholesterol,blood,Chromatography, Gas,Female,Humans,Kidney Failure, Chronic,Lipid Peroxidation,physiology,Male,Methylation,Middle Aged

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ScienceOpen disciplines: Chemistry

Keywords: Aged, Cholesterol, blood, Chromatography, Gas, Female, Humans, Kidney Failure, Chronic, Lipid Peroxidation, physiology, Male, Methylation, Middle Aged

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Oxysterols are increased in plasma of end-stage renal disease patients.

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Karger: Nephrology

Most cited references 8

NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells.

Oxysterols and atherosclerosis

7-ketocholesterol induces protein ubiquitination, myelin figure formation, and light chain 3 processing in vascular smooth muscle cells.

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