Document Detail

Oxysterol mixtures prevent proapoptotic effects of 7-ketocholesterol in macrophages: implications for proatherogenic gene modulation.
MedLine Citation:
PMID:  14977888     Owner:  NLM     Status:  MEDLINE    
Oxysterols are common components of oxidized low-density lipoprotein and accumulate in the core of fibrotic plaques as a mixture of cholesterol and cholesteryl ester oxidation products. The proapoptotic effects of a biologically representative mixture of oxysterols was compared with equimolar amounts of 7-ketocholesterol and unoxidized cholesterol. The oxysterol mixture in a concentration range actually detectable in hypercholesterolemic patients did not stimulate programmed cell death in cultivated murine macrophages. Unoxidized cholesterol also produced no effect. 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. Subsequent experiments showed that when 7-ketocholesterol was administered to cells together with another oxysterol, namely 7betaOH-cholesterol, the strong proapoptotic effect of 7-ketocholesterol was markedly attenuated. As regards the mechanism underlying this quenching, we found that the combined oxysterol treatment counteracted the ability of 7-ketocholesterol, when administered alone, to strongly up-regulate the steady-state levels of reactive oxygen species (ROS) without interfering with sterol uptake. Furthermore, this increase in intracellular ROS appeared to be responsible for the up-regulation of proapoptotic factor, p21, after treatment with 7-ketocholesterol but not in cells challenged with the oxysterol mixture. Competition among oxysterols, apparently at the level of NADPH oxidase, diminishes the ROS induction and direct toxicity that is evoked by specific oxysterols. As a consequence, a more subtle gene modulation by oxysterols becomes facilitated in vascular cells.
Fiorella Biasi; Gabriella Leonarduzzi; Barbara Vizio; Daniella Zanetti; Alex Sevanian; Barbara Sottero; Veronica Verde; Barbara Zingaro; Elena Chiarpotto; Giuseppe Poli
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Publication Detail:
Type:  Journal Article     Date:  2004-02-20
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  18     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2004 Apr 
Date Detail:
Created Date:  2004-03-31     Completed Date:  2004-07-15     Revised Date:  2012-02-15    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  693-5     Citation Subset:  IM    
Department of Clinical and Biological Sciences, University of Torino, S. Luigi Gonzaga Hospital, Torino, Italy.
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MeSH Terms
Apoptosis / drug effects*
Arteriosclerosis / genetics,  metabolism
Caspase 3
Caspases / metabolism
Cell Line
Cholesterol / pharmacology
Gene Expression Regulation
Hydroxycholesterols / pharmacology
Ketocholesterols / antagonists & inhibitors*
Macrophages / cytology,  drug effects*,  metabolism
Mitochondria / drug effects,  metabolism
Models, Biological
Reactive Oxygen Species / metabolism
Sterols / chemistry,  pharmacology*
Reg. No./Substance:
0/Hydroxycholesterols; 0/Ketocholesterols; 0/Reactive Oxygen Species; 0/Sterols; 566-26-7/cholest-5-en-3 beta,7 alpha-diol; 566-28-9/7-ketocholesterol; 57-88-5/Cholesterol; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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