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Titolo:
LDL downregulates CYP51 in porcine vascular endothelial cells and in the arterial wall through a sterol regulatory element binding protein-2-dependent mechanism
Autore:
Rodriguez, C; Martinez-Gonzalez, J; Sanchez-Gomez, S; Badimon, L;
Indirizzi:
UAB, Inst Recerca Hosp Santa Creu I Sant Pau, CSIC,Inst Invest Biomed, Cardiovasc Res Ctr, Barcelona, Spain UAB Barcelona Spain Invest Biomed, Cardiovasc Res Ctr, Barcelona, Spain
Titolo Testata:
CIRCULATION RESEARCH
fascicolo: 3, volume: 88, anno: 2001,
pagine: 268 - 274
SICI:
0009-7330(20010216)88:3<268:LDCIPV>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
LOW-DENSITY-LIPOPROTEIN; BOUND TRANSCRIPTION FACTOR; LEUCINE ZIPPER PROTEIN; LANOSTEROL 14-ALPHA-DEMETHYLASE; SYNTHASE PROMOTER; RECEPTOR GENE; NITRIC-OXIDE; CIS-ELEMENTS; EXPRESSION; SREBP-1;
Keywords:
SREBP-2; endothelium; CYP51; LDL; hypercholesterolemia;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Badimon, L CSIC, IIBB, C Jordi Girona 18-26, ES-08034 Barcelona, Spain CSIC C Jordi Girona 18-26 Barcelona Spain ES-08034 lona, Spain
Citazione:
C. Rodriguez et al., "LDL downregulates CYP51 in porcine vascular endothelial cells and in the arterial wall through a sterol regulatory element binding protein-2-dependent mechanism", CIRCUL RES, 88(3), 2001, pp. 268-274

Abstract

Hypercholesterolemia is associated with endothelial dysfunction and atherosclerotic lesion formation. By mRNA-differential display analysis, we have identified lanosterol Id,alpha -demethylase (CYP51) as a gene highly regulated by native LDLs (nLDLs) in endothelial cells. CYP51 is a cytochrome P-450 enzyme involved in the postsqualene phases of cholesterol biosynthesis. CYP51 mRNA levels decrease in nLDL-treated cells in a dose- and time-dependent manner (9-fold after 24 hours with 180 mg of LDL cholesterol per deciliter), an effect that is blocked by cycloheximide. In parallel, sterol regulatory element (SRE) binding protein-2 (SREBP-2) expression falls (10-fold), without alteration in SREBP-1 level. N-Acetyl-leucyl-leucyl-norleucinal, which inhibits catabolism of the active form of SREBPs, abolished the effect of high concentrations of nLDL on CYP51 expression. Gel-shift assays performed with the SRE of the cyp51 gene (cyp51-SRE) revealed a diminished SREBP-SRE interaction in LDL-treated cells. Moreover, nLDLs downregulate CYP51 promoter activity in transfection assays. Thus, atherogenic levels of nLDL downregulate endothelial CYP51 mRNA levels through a reduction in SRE-SREBP-2interaction. Additionally, SREBP-2 and CYP51 mRNA levels are decreased in the arterial wall of hypercholesterolemic pigs. In summary, we have described for the first time, both in in vivo and in vitro systems, that CYP51 is expressed in the vascular wall and that it is downregulated together with SREBP-2 by high levels of nLDL. Because this transcription factor controls multiple cell lipid metabolism pathways, its regulation by nLDL could play akey role in lipid-mediated endothelial dysfunction.

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Documento generato il 30/03/20 alle ore 19:30:38