© 2001 American Heart Association, Inc.
Vascular Biology |
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
From the Cardiovascular Research Center, IIBB/CSIC-Institut de Recerca del Hospital de la Santa Creu i Sant Pau-UAB, Barcelona, Spain.
Correspondence to Prof Lina Badimon, Laboratorio de Investigación Cardiovascular, Hospital de la Santa Creu i Sant Pau, Avda. Sant Antonio Maria Claret #167, 08025 Barcelona, Spain. E-mail lbmucv{at}cid.csic.es
Abstract—Atherogenic
levels of native low density lipoproteins (nLDLs) decrease the
bioavailability of endothelium-derived NO and
downregulate endothelial NO synthase (eNOS) expression
in cultured human endothelial cells. Here, we show that
simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A
reductase inhibitor, within the therapeutic range (0.01 to
1 µmol/L) prevented the downregulation of eNOS mRNA and protein
promoted by nLDL (180 mg cholesterol/dL, 48 hours) in human
umbilical vein endothelial cells. This effect of
simvastatin was completely reversed by mevalonate, the
product of the reaction, and to a lesser extent by farnesol and
geranyl geraniol. Simvastatin significantly stabilized eNOS
mRNA in cells treated with nLDL during 48 hours (eNOS mRNA half-life
11 hours in controls versus >24 hours in nLDL per 0.1 µmol/L
simvastatin–treated cells). The downregulation of eNOS by
nLDL was abrogated by cycloheximide, an inhibitor of
protein synthesis, and by
N-acetyl-leucyl-leucyl-norleucinal,
a protease inhibitor that reduces the catabolism of sterol
regulatory element binding proteins. Sterol deprivation
increased the downregulation produced by nLDL on eNOS and sterol
regulatory element binding protein-2 expression levels. However, no
differential modulation of the retardation bands corresponding to the
putative sterol-responsive element present in the eNOS promoter was
detected by electrophoretic mobility shift assay. Our results suggest
that nLDL promote eNOS downregulation operating at a transcriptional
level, whereas simvastatin prevents such an effect through
a posttranscriptional
mechanism.
Key Words: endothelial cells • low density lipoproteins • NO synthase • HMG-CoA reductase inhibitors • simvastatin
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