© 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
This article has been cited by other articles:
 |
|
 |
|
  J. Martinez-Gonzalez, R. Rodriguez-Rodriguez, M. Gonzalez-Diez, C. Rodriguez, M. D. Herrera, V. Ruiz-Gutierrez, and L. Badimon Oleanolic Acid Induces Prostacyclin Release in Human Vascular Smooth Muscle Cells through a Cyclooxygenase-2-Dependent Mechanism J. Nutr., March 1, 2008; 138(3): 443 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Maas, E. Schwedhelm, L. Kahl, H. Li, R. Benndorf, N. Luneburg, U. Forstermann, and R. H. Boger Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide-Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia Clin. Chem., February 1, 2008; 54(2): 292 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Simionescu Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 266 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nagaoka, A. Takahashi, E. Sato, N. Izumi, T. W. Hein, L. Kuo, and A. Yoshida Effect of systemic administration of simvastatin on retinal circulation. Arch Ophthalmol, May 1, 2006; 124(5): 665 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Niwano, M. Arai, N. Koitabashi, S. Hara, A. Watanabe, K. Sekiguchi, T. Tanaka, T. Iso, and M. Kurabayashi Competitive Binding of CREB and ATF2 to cAMP/ATF Responsive Element Regulates eNOS Gene Expression in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1036 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Boos, R. A. Anderson, and G. Y.H. Lip Is atrial fibrillation an inflammatory disorder? Eur. Heart J., January 2, 2006; 27(2): 136 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Garcia-Ramirez, J. Martinez-Gonzalez, J. O. Juan-Babot, C. Rodriguez, and L. Badimon Transcription Factor SOX18 Is Expressed in Human Coronary Atherosclerotic Lesions and Regulates DNA Synthesis and Vascular Cell Growth Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2398 - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. G. Herman and S. Moncada Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis Eur. Heart J., October 1, 2005; 26(19): 1945 - 1955. [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]
|
|
|
|
|
|
J. S. Perona, J. Martinez-Gonzalez, J. M. Sanchez-Dominguez, L. Badimon, and V. Ruiz-Gutierrez The Unsaponifiable Fraction of Virgin Olive Oil in Chylomicrons from Men Improves the Balance between Vasoprotective and Prothrombotic Factors Released by Endothelial Cells J. Nutr., December 1, 2004; 134(12): 3284 - 3289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Davignon Beneficial Cardiovascular Pleiotropic Effects of Statins Circulation, June 15, 2004; 109(23_suppl_1): III-39 - III-43. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 D. Pierre-Paul and V. Gahtan Noncholesterol-Lowering Effects of Statins Vascular and Endovascular Surgery, September 1, 2003; 37(5): 301 - 313. [Abstract] [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]
|
|
|
|
 |
|
 R. M. Bell and D. M. Yellon Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway J. Am. Coll. Cardiol., February 5, 2003; 41(3): 508 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fleming and R. Busse Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R1 - R12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Napoli, L. O. Lerman, F. de Nigris, J. Loscalzo, and L. J. Ignarro Glycoxidized low-density lipoprotein downregulates endothelial nitricoxide synthase in human coronary cells J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1515 - 1522. [Abstract] [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]
|
|