Disease relevance of SC 4722

• Over a defined range of concentrations (0-5 mg/ml), efflux of 7-ketocholesterol was preferred over that of cholesterol and occurred without cell toxicity [1].
• In the present study, we investigated the cytotoxic effects of 7beta-hydroxycholesterol (7betaOH), 7-ketocholesterol (7keto), 25-hydroxycholesterol (25OH), and 27-hydroxycholesterol (27OH) on U937 monocytic cells, both individually and in atheroma-relevant mixtures mimicking the oxysterol composition reported in human atheroma lesions [2].
• Levels of 7-oxocholesterol in cerebrospinal fluid are more than one thousand times lower than reported in multiple sclerosis [3].
• Plasma 7-ketocholesterol was significantly higher in patients with diabetes (31.6+/-2.8 ng/mL) or hypercholesterolemia (52.3+/-5.9) than in the control group (22.4+/-1.2) [4].
• Here, to elucidate the roles of oxysterols in brain inflammation, we treated lipopolysaccharide-stimulated rat brain astrocytes with two oxysterols, 7-ketocholesterol and 22(R)-hydroxycholesterol [5].

High impact information on SC 4722

• The concentrations of the breakdown product 7-ketocholesterol detected in the CSF of MS patients were capable of inducing neuronal damage via the activation and migration of microglial cells in living brain tissue [6].
• 7-ketocholesterol rapidly entered the nucleus and activated poly(ADP-ribose)-polymerase (PARP)-1, followed by the expression of migration-regulating integrins CD11a and intercellular adhesion molecule 1 [6].
• NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells [7].
• 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) [7].
• IFN-beta alone did not induce apoptosis; thus, 7kchol-induced release of IFN-beta was necessary but not sufficient for optimal apoptosis [8].

Chemical compound and disease context of SC 4722

• Because of recent evidence that 7-ketocholesterol and 7-hydroxycholesterol are toxic species in copper-oxidized LDL, inhibition of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase was hypothesized as a mechanism of toxicity [9].
• Quantification of these unesterified oxysterols in LDL extracts and comparison with the toxicity of authentic standards indicate that 7-ketocholesterol and 7-hydroxycholesterol are present in Ox-LDL at levels sufficient to account for its toxicity to SMCs [10].

Biological context of SC 4722

• 7-Ketocholesterol (7kchol) is prominent in atherosclerotic lesions where apoptosis occurs [8].
• A neutralizing antibody against beta interferon (IFN-beta) blunted Ser(727) phosphorylation and apoptosis after 7kchol treatment; cells deficient in an IFN-beta receptor subunit exhibited blunted apoptosis [8].
• Therefore, the ability to induce cell death of structurally related oxysterols, such as those oxidized at C7(7alpha-, 7beta-hydroxycholesterol, and 7-ketocholesterol), was investigated on U937 cells at different times of treatment in a concentration range of 5-80 microg/ml [11].
• We have identified 7-ketocholesterol (7-KC) as an endogenous modulator that inhibits transactivation by the arylhydrocarbon receptor (AhR) through competitive binding against xenobiotic ligands [12].
• Apoptotic cells, recognized by fragmented and/or condensed nuclei after staining with Hoechst 33342 or Giemsa, were mainly detected among non-adherent cells, and agarose gel electrophoresis revealed a typical internucleosomal DNA fragmentation among 7-ketocholesterol-treated cells [13].

Anatomical context of SC 4722

• Moreover, this Ca(2+) increase appears related to the incorporation of 7-ketocholesterol into lipid raft domains of the plasma membrane, followed by the translocation of transient receptor potential calcium channel 1, a component of the store operated Ca(2+) entry channel, to rafts [14].
• Sterol 27-hydroxylase acts on 7-ketocholesterol in human atherosclerotic lesions and macrophages in culture [15].
• Hydroxypropyl-beta-cyclodextrin-mediated efflux of 7-ketocholesterol from macrophage foam cells [1].
• In this study, we demonstrate that, in the murine macrophage-like cell line P388D1, oxysterols (25-hydroxycholesterol and 7-ketocholesterol) induced the degradation of the prosurvival protein kinase AKT (protein kinase B) [16].
• Induction of similar features of apoptosis in human and bovine vascular endothelial cells treated by 7-ketocholesterol [13].

Associations of SC 4722 with other chemical compounds

• Glutathione is implied in the control of 7-ketocholesterol-induced apoptosis, which is associated with radical oxygen species production [17].
• Ceramide generation occurring during 7beta-hydroxycholesterol- and 7-ketocholesterol-induced apoptosis is caspase independent and is not required to trigger cell death [11].
• The physical solubilization of 7-ketocholesterol by the cyclodextrin was much greater than that of cholesterol, in accordance with its differential effects on efflux [1].
• In contrast, the half-life is strongly reduced when HTC cells are incubated with cycloheximide plus maximal concentrations of 25-hydroxycholesterol, 7-ketocholesterol, or cholestenone, resulting in t1/2 values of 24, 36, and 60 min, respectively [18].
• Sterol efflux is impaired from macrophage foam cells selectively enriched with 7-ketocholesterol [19].

Gene context of SC 4722

• TNF-alpha activates death pathway in human aorta smooth muscle cell in the presence of 7-ketocholesterol [20].
• Sterol 27-hydroxylase (CYP27A1) is a mitochondrial P-450 enzyme with broad substrate specificity for C27 sterols including 7-ketocholesterol (7kCh) [21].
• Preincubation of macrophages with atorvastatin, cholesterol, 25-, 27-hydroxycholesterol, and 7-ketocholesterol reduced the level of TNF-alpha to 10, 61, 13, 64.5, and 82%, respectively [22].
• 7-ketocholesterol enhances surface expression of ICAM-1 and VCAM-1 as determined by EIA, induces their mRNA expression by RT-PCR, and stimulates adhesiveness of HAECs to U937 monocytic cells [23].
• By contrast, when given alone, 7-ketocholesterol strongly stimulated the mitochondrial pathway of apoptosis with cytochrome c release, caspase-9 activation, and eventually caspase-3 activation [24].

Analytical, diagnostic and therapeutic context of SC 4722

• During 7-ketocholesterol-induced apoptosis, we also observed a rapid decrease in cellular GSH content, oxidation of polyunsaturated fatty acids, and a production of ROS by flow cytometry with the use of the dye 2', 7'-dichlorofluorescin-diacetate; both phenomena were inhibited by GSH [17].
• This was accompanied by increased levels of cholesterol, 24-hydroxycholesterol (product of cholesterol 24-hydroxylase enzymatic activity), and 7-ketocholesterol in homogenates of the degenerating hippocampus as detected by gas chromatography/mass spectrometry [25].
• Four specific side-chain oxidation products of proteins, and the lipid oxidation products 7-ketocholesterol and cholesterol ester alcohols and hydroperoxides, were quantified by HPLC in the same samples used for the iron measurements [26].
• Analysis by thin-layer chromatography demonstrated that oxysterols, including 7-ketocholesterol, in OX-LDL were transferred from OX-LDL to HDL during coincubation of these two lipoproteins [27].
• The cellular content of native cholesterol, individual cholesteryl esters, and 7-ketocholesterol was determined by high-performance liquid chromatography [28].

References