Relevance and mechanism of oxysterol stereospecifity in coronary artery disease

Rimner, Andreas; Makdessi, Samar Al; Sweidan, H.; Wischhusen, Jörg; Rabenstein, Björn; Shatat, Khaula; Mayer, Petra; Spyridopoulos, Ioakim

doi:10.1016/j.freeradbiomed.2004.11.016

Cited by 59 publications

(45 citation statements)

References 29 publications

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“…As caspase-3/7 and -8 activity, cytochrome c release, Bid and ICAD degradation were more pronounced in the presence of 7␤-OH, our data are in agreement with previous investigations reporting that 7␤-OH is a more potent inducer of apoptosis than 7-keto [48,49]. This stereospecificity hints at the existence of a putative oxysterol receptor, or direct effects on membrane organization, mainly at raft level that orchestrates signal transduction [7,50]. Moreover, since caspases-7 and -8 can be activated either by caspase-3, -8, or -9, and by caspase-3, -7, or -9, respectively [14], and since PARP and ICAD degradation (leading subsequently to internucleosomal DNA cleavage) can involve the executioner caspase-3 or -7, which have overlapping substrate specificities containing a DXXD motif [14], it was important to make precise the role of caspase-3 in oxysterol-induced cell death.…”

Section: Discussionsupporting

confidence: 93%

“…Oxysterols such as 7-ketocholesterol (7-keto) and 7␤-hydroxycholesterol (7␤-OH) (present at enhanced levels in atherosclerotic plaques [5] and plasma of patients with higher atherogenic risk or with coronary artery disease) [6,7] are known to mediate the various effects of Ox-LDL [4] (when taken in isolation or used in mixture [5,8]). These compounds are capable of inducing a complex mode of cell death, combined with mechanisms of apoptosis [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Activation of caspase-3-dependent and -independent pathways during 7-ketocholesterol- and 7β-hydroxycholesterol-induced cell death: A morphological and biochemical study

Prunet

Lemaire-Ewing

Ménétrier

et al. 2005

J. Biochem. Mol. Toxicol.

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On treatment with 7-ketocholesterol (7-keto) or 7beta-hydroxycholesterol (7beta-OH), which are major oxysterols in atherosclerotic plaques, the simultaneous identification of oncotic and apoptotic cells suggests that these compounds activate different metabolic pathways leading to various modes of cell death. With U937, MCF-7 (caspase-3 deficient), MCF-7/c3 cells (stably transfected with caspase-3), we demonstrate that caspase-3 is essential for caspase-9, -7, -8 activation, for Bid degradation mediating mitochondrial cytochrome c release, for cleavage of poly(ADP-ribose) polymerase and inhibitor of the caspase-activated deoxyribonuclease, and, at least in part, for internucleosomal DNA fragmentation. The crucial role of caspase-3 was supported by the use of z-VAD-fmk and z-DEVD-fmk, which abolished apoptosis and the associated events. However, inactivation or lack of caspase-3 did not inhibit 7-keto- and 7beta-OH-induced cell death characterized by staining with propidium iodide, loss of mitochondrial potential. The mitochondrial release of apoptosis-inducing factor and endonuclease G was independent of the caspase-3 status, which conversely played major roles in the morphological aspects of dead cells. We conclude that caspase-3 is essential to trigger 7-keto- and 7beta-OH-induced apoptosis, that these oxysterols simultaneously activate caspase-3-dependent and/or -independent modes of cell death.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Activation of caspase-3-dependent and -independent pathways during 7-ketocholesterol- and 7β-hydroxycholesterol-induced cell death: A morphological and biochemical study

Prunet

Lemaire-Ewing

Ménétrier

et al. 2005

J. Biochem. Mol. Toxicol.

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“…Oxysterols, which bind to this receptor, are products of cholesterol oxidation and their levels are also associated with CAD. 38 All of these candidate genes lie outside the 1-LOD support interval for the peak LOD score (see figures), but it has been found that linkage peaks often lie quite distant to disease loci. 39 In summary, we report stronger evidence of linkage to CAD of the initially reported locus on chromosome 2 when allowing for hypercholesterolemia, the evidence for linkage being confined to subjects without hypercholesterolemia.…”

Section: Discussionmentioning

confidence: 99%

Enhanced linkage of a locus on chromosome 2 to premature coronary artery disease in the absence of hypercholesterolemia

et al. 2006

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Linkage studies of complex diseases have so far had limited success in producing significant and replicable results, in part owing to genetic heterogeneity. We recently reported the results of a large genome-wide linkage scan for coronary artery disease (CAD) based on 1933 families. The greatest evidence for linkage was to a region of chromosome 2, with a logarithm of odds (LOD) score of 1.86, based on the nonparametric S ALL statistic, which did not reach genome-wide significance (P40.3). Inclusion of a covariate in linkage analysis can be a powerful method of accounting for disease heterogeneity. As CAD is a heterogeneous disease, we carried out a linkage analysis of chromosome 2 incorporating covariates. Increased evidence for linkage was found when hypercholesterolemia was considered (LOD score including covariate of 4.4) reaching genome-wide significance as assessed by simulation (P ¼ 0.04). Results showed that the original evidence for linkage was largely attributable to the subset of 108 nonhypercholesterolemic affected sibling pairs. In separate linkage analyses of subsets of hypercholesterolemic and non-hypercholesterolemic sibling pairs, the maximum LOD scores were 1.09 in the former group and 3.74 in the latter. This result illustrates the potential to increase the power of linkage analysis in the presence of heterogeneity by inclusion of covariates. This linked locus on chromosome 2 should now be investigated further to identify the gene(s) influencing risk of CAD in subjects with a normal level of total cholesterol. Candidate genes include the interleukin 1 cluster and two potential regulators of high-density lipoprotein cholesterol level, PLA2R1 and OSBPL6.

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“…The mutagenicity of cholesterol epoxide in V79 Chinese hamster lung Wbroblasts (Black and Douglas 1972; Reddy and Wynder 1977;Sevanian and Peterson 1984) suggests that the ChEH might play a role in protecting cells from these steroid toxicants, however, the cholesterol epoxides are quiet stable and the corresponding cholestantriols are themselves cytotoxic (Wilson et al 1997;Vejux et al 2007). Further, cholesterol epoxides are implicated in apoptosis (Ryan et al 2004), as well as vascular function and coronary artery disease (Rimner et al 2005) because they are found upregulated in arteriosclerotic lesions. Only a complete characterisation of ChEH can help to fully understand the physiological role of this enzyme.…”

Section: Other Mammalian Epoxide Hydrolasesmentioning

confidence: 99%

Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

2009

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Epoxide hydrolases catalyse the hydrolysis of electrophilic-and therefore potentially genotoxic-epoxides to the corresponding less reactive vicinal diols, which explains the classiWcation of epoxide hydrolases as typical detoxifying enzymes. The best example is mammalian microsomal epoxide hydrolase (mEH)-an enzyme prone to detoxiWcation-due to a high expression level in the liver, a broad substrate selectivity, as well as inducibility by foreign compounds. The mEH is capable of inactivating a large number of structurally diVerent, highly reactive epoxides and hence is an important part of the enzymatic defence of our organism against adverse eVects of foreign compounds. Furthermore, evidence is accumulating that mammalian epoxide hydrolases play physiological roles other than detoxiWcation, particularly through involvement in signalling processes. This certainly holds true for soluble epoxide hydrolase (sEH) whose main function seems to be the turnover of lipid derived epoxides, which are signalling lipids with diverse functions in regulatory processes, such as control of blood pressure, inXammatory processes, cell proliferation and nociception. In recent years, the sEH has attracted attention as a promising target for pharmacological inhibition to treat hypertension and possibly other diseases. Recently, new hitherto uncharacterised epoxide hydrolases could be identiWed in mammals by genome analysis. The expression pattern and substrate selectivity of these new epoxide hydrolases suggests their participation in signalling processes rather than a role in detoxiWcation. Taken together, epoxide hydrolases (1) play a central role in the detoxiWcation of genotoxic epoxides and (2) have an important function in the regulation of physiological processes by the control of signalling molecules with an epoxide structure.

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Relevance and mechanism of oxysterol stereospecifity in coronary artery disease

Cited by 59 publications

References 29 publications

Activation of caspase-3-dependent and -independent pathways during 7-ketocholesterol- and 7β-hydroxycholesterol-induced cell death: A morphological and biochemical study

Activation of caspase-3-dependent and -independent pathways during 7-ketocholesterol- and 7β-hydroxycholesterol-induced cell death: A morphological and biochemical study

Enhanced linkage of a locus on chromosome 2 to premature coronary artery disease in the absence of hypercholesterolemia

Mammalian epoxide hydrolases in xenobiotic metabolism and signalling

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