© 2001 American Heart Association, Inc.
Molecular Medicine |
LDL Downregulates CYP51 in Porcine Vascular Endothelial Cells and in the Arterial Wall Through a Sterol Regulatory Element Binding Protein-2–Dependent Mechanism
From the Cardiovascular Research Center, Instituto de Investigaciones Biomédicas de Barcelona/Consejo Superior de Investigaciones Cientificas–Institut de Recerca Hospital de la Santa Creu i Sant Pau–UAB, Barcelona, Spain.
Correspondence to Dr Lina Badimon, IIBB-CSIC, C/Jordi Girona, 18-26, 08034 Barcelona, Spain. E-mail lbmucv{at}cid.csic.es
Abstract—Hypercholesterolemia
is associated with endothelial dysfunction and atherosclerotic lesion
formation. By mRNA–differential display analysis, we have identified
lanosterol 14
-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-2 interaction. 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 a key role in
lipid-mediated endothelial
dysfunction.
Key Words: SREBP-2 • endothelium • CYP51 • LDL • hypercholesterolemia
This article has been cited by other articles:
 |
|
 |
|
  C. Rodriguez, J. F. Alcudia, J. Martinez-Gonzalez, A. Guadall, B. Raposo, S. Sanchez-Gomez, and L. Badimon Statins normalize vascular lysyl oxidase down-regulation induced by proatherogenic risk factors Cardiovasc Res, August 1, 2009; 83(3): 595 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Y. Tamboli, K. Prager, D. R. Thal, K. M. Thelen, I. Dewachter, C. U. Pietrzik, P. St. George-Hyslop, S. S. Sisodia, B. De Strooper, M. T. Heneka, et al. Loss of {gamma}-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis J. Neurosci., November 12, 2008; 28(46): 12097 - 12106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fink, J. Acimovic, T. Rezen, N. Tansek, and D. Rozman Cholesterogenic Lanosterol 14{alpha}-Demethylase (CYP51) Is an Immediate Early Response Gene Endocrinology, December 1, 2005; 146(12): 5321 - 5331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Crespo, J. Martinez-Gonzalez, J. Rius, and L. Badimon Simvastatin inhibits NOR-1 expression induced by hyperlipemia by interfering with CREB activation Cardiovasc Res, August 1, 2005; 67(2): 333 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Llorente-Cortes and L. Badimon LDL Receptor-Related Protein and the Vascular Wall: Implications for Atherothrombosis Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 497 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rius, J. Martinez-Gonzalez, J. Crespo, and L. Badimon Involvement of Neuron-Derived Orphan Receptor-1 (NOR-1) in LDL-Induced Mitogenic Stimulus in Vascular Smooth Muscle Cells: Role of CREB Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 697 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Rodriguez, B. Raposo, J. Martinez-Gonzalez, V. Llorente-Cortes, G. Vilahur, and L. Badimon Modulation of ERG25 expression by LDL in vascular cells Cardiovasc Res, April 1, 2003; 58(1): 178 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Martinez-Gonzalez, J. Rius, A. Castello, C. Cases-Langhoff, and L. Badimon Neuron-Derived Orphan Receptor-1 (NOR-1) Modulates Vascular Smooth Muscle Cell Proliferation Circ. Res., January 10, 2003; 92(1): 96 - 103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Llorente-Cortes, M. Otero-Vinas, S. Sanchez, C. Rodriguez, and L. Badimon Low-Density Lipoprotein Upregulates Low-Density Lipoprotein Receptor-Related Protein Expression in Vascular Smooth Muscle Cells: Possible Involvement of Sterol Regulatory Element Binding Protein-2-Dependent Mechanism Circulation, December 10, 2002; 106(24): 3104 - 3110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Bank and V. W.M. van Hinsbergh Lysyl Oxidase: New Looks on LOX Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1365 - 1366. [Full Text] [PDF]
|
|
|
|
|
|
C. Rodriguez, B. Raposo, J. Martinez-Gonzalez, L. Casani, and L. Badimon Low Density Lipoproteins Downregulate Lysyl Oxidase in Vascular Endothelial Cells and the Arterial Wall Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1409 - 1414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Martinez-Gonzalez, B. Raposo, C. Rodriguez, and L. Badimon 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition Prevents Endothelial NO Synthase Downregulation by Atherogenic Levels of Native LDLs : Balance Between Transcriptional and Posttranscriptional Regulation Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 804 - 809. [Abstract] [Full Text] [PDF]
|
|