Selective role of sterol regulatory element binding protein isoforms in aggregated LDL-induced vascular low density lipoprotein receptor-related protein-1 expression

被引:29
作者
Costales, P. [1 ]
Aledo, R. [1 ,6 ]
Vernia, S. [2 ]
Das, A. [3 ,4 ]
Shah, V. H. [5 ]
Casado, M. [2 ]
Badimon, L. [1 ,6 ]
Llorente-Cortes, V. [1 ]
机构
[1] Hosp Santa Creu & San Pau UAB, CSIC ICCC, Barcelona Cardiovasc Res Ctr, Barcelona 08025, Spain
[2] CSIC, IBV, Valencia, Spain
[3] Loma Linda Univ, Sch Med, Dept Basic Sci, Div Biochem, Loma Linda, CA 92350 USA
[4] Loma Linda Univ, Sch Med, Dept Med, Div Regenerat Med, Loma Linda, CA 92350 USA
[5] Mayo Clin, GI Res Unit, Rochester, MN 55905 USA
[6] CIBEROBN, Cordoba, Spain
关键词
Aggregated LDL; LRP1; SREBP-1a; SREBP-1c; SREBP-2; Human VSMC; SMOOTH-MUSCLE-CELLS; LIVER-X-RECEPTOR; PROTEIN-2-DEPENDENT MECHANISM; TYROSINE PHOSPHORYLATION; ATHEROSCLEROTIC LESIONS; SCAVENGER RECEPTOR; SP1-LIKE PROTEIN; LIPID-SYNTHESIS; GENE PROMOTER; TRANSCRIPTION;
D O I
10.1016/j.atherosclerosis.2010.09.034
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Low density lipoprotein receptor-related protein (LRP1) is upregulated in vascular smooth muscle cells by intravascular aggregated LDL (agLDL) - LDL trapped in the arterial intima and systemic LDL. LRP1 upregulation in hypercholesterolemic aortas is concomitant with SREBP downregulation. However, the specific role of SREBP isoforms in LRP1 transcription and LDL-induced LRP1 upregulation in human vascular smooth muscle cells (VSMC) is unknown. In the present study were port that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression. Gel mobility shift and ChIP assays demonstrated that SREBP-1a, SREBP-1c and SREBP-2 were able to bind to three putative SRE sequences; SRE-A (-1042 to -1028), SRE-B (-115 to -101) and SREC (+226 to +234). ChIP assays demonstrated that agLDL (100 mu g/mL, 24 h) significantly and specifically decreased SREBP-2 binding to the LRP1 promoter. Luciferase assays demonstrated that agLDL increased the transcriptional activity of A/B or A/C double mutants but failed to increase that of the double B/C mutant. Our results show that both SREBP-1 and SREBP-2 negatively modulated LRP1 transcription. Furthermore, agLDL exerted an upregulatory effect on LRP1 expression by decreasing SREBP-2 binding to LRP1 promoter. Two SRE-like sequences control the response of LRP1 to agLDL. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:458 / 468
页数:11
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