Oxysterols and atherosclerosis

Brown, Andrew; Jessup, Wendy

doi:10.1016/s0021-9150(98)00196-8

Cited by 827 publications

(719 citation statements)

References 208 publications

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“…9 The enzyme has been implicated to play a role in diseases such as prostate cancer 3 and atherosclerosis. 16 Here, we show for the first time a polymorphism in the CYP7B1 gene that is associated with an altered promoter activity. The fact that the promoter polymorphism identified here is associated with an altered phenotype provides an important SNP tool for future association studies.…”

Section: Determination Of the Allele Frequencymentioning

confidence: 70%

A functional C–G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians

et al. 2004

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Cytochrome P450 (CYP) 7B1 is involved in many metabolic processes including androgen metabolism. Genetic variation in the CYP7B1 gene may play a role in predisposition to prostate cancer. Here, we screened the human CYP7B1 gene for possible polymorphisms. Only one single polymorphism was detected, a C-G change in the promoter -104 base pair from the transcription start site. The allele frequency was investigated in Swedish men and compared to a Korean population, as it is known that the frequency of prostate cancer is low among Orientals. We found that the frequency of the G-allele was 4.04% in Swedes (n ¼ 150) but only 0.33% among Koreans (n ¼ 153). Computer analysis indicated that the two variants bind with different affinities to a CCAAT-box binding protein. Expression studies with reporter constructs showed significantly higher transcriptional activity of the G variant in Hek293 cells (2.7-fold, Po0.05). In conclusion, we report here for the first time the detection of a single polymorphism in the CYP7B1 gene. This polymorphism is associated with phenotypic differences in an expression system and a widely different allele frequency in two ethnic populations, with great differences in the incidence of prostate cancer.

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Section: Determination Of the Allele Frequencymentioning

confidence: 70%

A functional C–G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians

et al. 2004

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“…In lungs, specific oxidation of the active site in the ␣-1-antiprotease leads to proteolysis of elastic fibers in the extracellular matrix [14]. Due to the short-term incubation required to observe the fibers' damage in our experiments, we do not expect an activation of gene expression to be involved [9,11,12]. The ox-LDL-induced activation of expression of metalloproteinases has been reported to peak in 6 h [12], after exposure to a concentration of LDL hydroperoxides much higher than that in the LDL we used.…”

Section: Discussionmentioning

confidence: 91%

“…Aneurysm formation and evolution involves degradation of matrix proteins [4]. Endothelial dysfunction, eventually evolving to vascular damage, can be reproduced in vitro by low-density lipoprotein (LDL), oxidatively modified to various extents [5][6][7][8][9]. Endothelial dysfunctions encompass the alteration of the endothelial barrier and the expression of adhesion molecules recruiting macrophages, which transmigrate to the subendothelial space together with LDL.…”

Section: Introductionmentioning

confidence: 99%

“…Endothelial dysfunctions encompass the alteration of the endothelial barrier and the expression of adhesion molecules recruiting macrophages, which transmigrate to the subendothelial space together with LDL. Focus has been directed to the presence of lipid hydroperoxides or oxysterols in LDL [8,9], on LDL particle size [6], on a covalent linkage to apo(a) [5], and on the role of inflammation in promoting gene activation [7]. Recent reports highlight the participation of LDL in the proteolysis of vascular extracellular matrix by inducing (i) a decrease of macrophage-specific tissue inhibitors of matrix-degrading metalloproteinases through the modulation of interleukin-8 [10]; (ii) the upregulation of expression of metalloproteinase-9 in monocytes, together with the downregulation of the metalloproteinase-1 inhibitor [11]; and (iii) the upregulation of the expression of the membrane type 1 matrix metalloproteinase in endothelial cells [12].…”

Section: Introductionmentioning

confidence: 99%

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Two-photon microscopy of aorta fibers shows proteolysis induced by LDL hydroperoxides

Parasassi

Durbin

et al. 2000

Free Radical Biology and Medicine

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Abstract-Oxidatively modified LDL mimics several aspects of atherogenesis. In this disease, degradation of the matrix proteins' network also occurs. By a new morphological ex vivo approach, not requiring sample processing, we explored the relationship between the degradation of matrix protein and oxidatively modified LDL. Two-photon excitation fluorescence microscopy images of fresh cross-section rings of rat aorta, acquired while the sample was maintained in a glucose-and oxygen-supplemented buffer, showed straight, parallel, thick, long extracellular matrix proteins. Traditional microscopic examination, requiring sample fixation and staining, shows smaller and curved fibers. Instead, we observed curved and broken fibers after a 30-min incubation of aorta with either LDL containing lipid hydroperoxides, or tert-butyl-hydroperoxide. The adhesion of LDL to the endothelium and its internalization was directly visualized by using a lipid fluorophore. The damage to aorta matrix proteins induced by LDL and tert-butylhydroperoxide was fully prevented by antioxidants, such as ascorbate or Trolox C, or inhibitors of proteases. The image spectroscopy of the fibers' autofluorescence (polarization and lifetime) revealed an increased mobility of the fluorescent cross-link in fibers. Damaged matrix proteins were also imaged in aorta samples from apolipoprotein E knock-out mice. Our ex vivo images directly visualized the activation of a fast redox-sensitive proteolytic process in the arterial wall triggered by lipid hydroperoxides in LDL.

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“…Some oxysterols are ligands to nuclear receptors, e.g., the liver X receptor (LXR) ␣ and ␤, and are considered to have important roles in the regulation of cholesterol and lipid metabolism and homeostasis [8 -15]. Some oxysterols have been proposed to mediate inflammatory events in the development of atherosclerotic lesions [16]. A variety of oxysterols are found in blood and tissues, exemplified by 27-hydroxycholesterol (C 5 -3␤,27-diol), 7␣-hydroxycholesterol (C 5 -3␤,7␣-diol), 24S-hydroxycholesterol (C 5 -3␤,24S-diol), and 4␤-hydroxycholesterol (C 5 -3␤,4␤-diol) (see Scheme 1 for steroid skeleton and numbering system).…”

mentioning

confidence: 99%

Analysis of oxysterols by electrospray tandem mass spectrometry

Griffiths

Wang

Alvélius

et al. 2006

J. Am. Soc. Mass Spectrom.

103

102

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Oxysterols are oxygenated derivatives of cholesterol. They are intermediates in cholesterol excretion pathways and may also be regarded as transport forms of cholesterol. The introduction of additional hydroxyl groups to the cholesterol skeleton facilitates the flux of oxysterols across the blood brain barrier, and oxysterols have been implicated in mediating a number of cholesterol-induced metabolic effects. Oxysterols are difficult to analyze by atmospheric pressure ionization mass spectrometry on account of the absence of basic or acidic functional groups in their structures. In this communication, we report a method for the derivatization and analysis of oxysterols by electrospray mass spectrometry. Oxysterols with a 3␤-hydroxy-⌬ 5 structure were converted by cholesterol oxidase to 3-oxo-⌬ 4 steroids and then derivatized with the Girard P reagent to give Girard P hydrazones, which were subsequently analyzed by tandem mass spectrometry. The improvement in sensitivity for the analysis of 25-hydroxycholesterol upon oxidation and derivatization was over 1000. (J Am Soc Mass Spectrom 2006, 17, 341-362)

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Oxysterols and atherosclerosis

Cited by 827 publications

References 208 publications

A functional C–G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians

A functional C–G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians

Two-photon microscopy of aorta fibers shows proteolysis induced by LDL hydroperoxides

Analysis of oxysterols by electrospray tandem mass spectrometry

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