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Oxysterol mixtures prevent proapoptotic effects of 7-ketocholesterol in macrophages: implications for proatherogenic gene modulation.
FASEB J. 2004 Apr; 18(6):693-5.FJ

Abstract

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.

Authors+Show Affiliations

Department of Clinical and Biological Sciences, University of Torino, S. Luigi Gonzaga Hospital, Torino, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14977888

Citation

Biasi, Fiorella, et al. "Oxysterol Mixtures Prevent Proapoptotic Effects of 7-ketocholesterol in Macrophages: Implications for Proatherogenic Gene Modulation." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 18, no. 6, 2004, pp. 693-5.
Biasi F, Leonarduzzi G, Vizio B, et al. Oxysterol mixtures prevent proapoptotic effects of 7-ketocholesterol in macrophages: implications for proatherogenic gene modulation. FASEB J. 2004;18(6):693-5.
Biasi, F., Leonarduzzi, G., Vizio, B., Zanetti, D., Sevanian, A., Sottero, B., Verde, V., Zingaro, B., Chiarpotto, E., & Poli, G. (2004). Oxysterol mixtures prevent proapoptotic effects of 7-ketocholesterol in macrophages: implications for proatherogenic gene modulation. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 18(6), 693-5.
Biasi F, et al. Oxysterol Mixtures Prevent Proapoptotic Effects of 7-ketocholesterol in Macrophages: Implications for Proatherogenic Gene Modulation. FASEB J. 2004;18(6):693-5. PubMed PMID: 14977888.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oxysterol mixtures prevent proapoptotic effects of 7-ketocholesterol in macrophages: implications for proatherogenic gene modulation. AU - Biasi,Fiorella, AU - Leonarduzzi,Gabriella, AU - Vizio,Barbara, AU - Zanetti,Daniella, AU - Sevanian,Alex, AU - Sottero,Barbara, AU - Verde,Veronica, AU - Zingaro,Barbara, AU - Chiarpotto,Elena, AU - Poli,Giuseppe, Y1 - 2004/02/20/ PY - 2004/2/24/pubmed PY - 2004/7/16/medline PY - 2004/2/24/entrez SP - 693 EP - 5 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 18 IS - 6 N2 - 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. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/14977888/Oxysterol_mixtures_prevent_proapoptotic_effects_of_7_ketocholesterol_in_macrophages:_implications_for_proatherogenic_gene_modulation_ L2 - https://doi.org/10.1096/fj.03-0401fje DB - PRIME DP - Unbound Medicine ER -