From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular
Division, Department of Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Mass.
Correspondence to James K. Liao, MD, Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, 221 Longwood Ave, LMRC-316, Boston, MA 02115. E-mail jkliao{at}bics.bwh.harvard.edu
Background—Oxidized low-density
lipoprotein (ox-LDL) causes endothelial dysfunction in
part by decreasing the availability of endothelial
nitric oxide (NO). Although HMG CoA reductase inhibitors
restore endothelial function by reducing serum
cholesterol levels, it is not known whether they can also
directly upregulate endothelial NO synthase
(ecNOS) activity.
Methods and Results—Human saphenous vein
endothelial cells were treated with ox-LDL (50 µg/mL
thiobarbituric acid reactive substances 12 to 16 nmol/mg) in the
presence of HMG CoA reductase inhibitors
simvastatin and lovastatin. In a time-dependent
manner, ox-LDL decreased ecNOS mRNA and protein levels (91±4% and
67±8% reduction after 72 hours, respectively). Both
simvastatin (1 µmol/L) and lovastatin
(10 µmol/L) upregulated ecNOS expression by 3.8-fold and
3.6-fold, respectively, and completely prevented its downregulation by
ox-LDL. These effects of simvastatin on ecNOS expression
correlated with changes in ecNOS activity. Although
L-mevalonate alone did not affect ecNOS expression,
cotreatment with L-mevalonate completely reversed ecNOS
upregulation by simvastatin. Actinomycin D studies revealed
that simvastatin stabilized ecNOS mRNA (
Conclusions—Inhibition of endothelial HMG CoA
reductase upregulates ecNOS expression predominantly by
posttranscriptional mechanisms. These findings suggest that HMG CoA
reductase inhibitors may have beneficial effects in
atherosclerosis beyond that attributed to the lowering
of serum cholesterol by increasing ecNOS activity.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Upregulation of Endothelial Nitric Oxide Synthase by HMG CoA Reductase Inhibitors
1/2,
43 versus 35 hours). Nuclear run-on assays and transient transfection
studies with a -1.6 kb ecNOS promoter construct showed that
simvastatin did not affect ecNOS gene transcription.
Key Words: atherosclerosis • endothelium-derived factors • lipoproteins • genes
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 N. Nair, R. K Oka, L. D Waring, E. M Umoh, C B. Taylor, and J. P Cooke Vascular compliance versus flow-mediated vasodilation: correlation with cardiovascular risk factors Vascular Medicine, November 1, 2005; 10(4): 275 - 283. [Abstract] [PDF]
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T. Murata, K. Kinoshita, M. Hori, M. Kuwahara, H. Tsubone, H. Karaki, and H. Ozaki Statin Protects Endothelial Nitric Oxide Synthase Activity in Hypoxia-Induced Pulmonary Hypertension Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2335 - 2342. [Abstract] [Full Text] [PDF]
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K. K. Ray, C. P. Cannon, R. Cairns, D. A. Morrow, N. Rifai, A. J. Kirtane, C. H. McCabe, A. M. Skene, C. M. Gibson, P. M. Ridker, et al. Relationship Between Uncontrolled Risk Factors and C-Reactive Protein Levels in Patients Receiving Standard or Intensive Statin Therapy for Acute Coronary Syndromes in the PROVE IT-TIMI 22 Trial J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1417 - 1424. [Abstract] [Full Text] [PDF]
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K. K. Ray and C. P. Cannon The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1425 - 1433. [Abstract] [Full Text] [PDF]
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M. D.M. Engelmann and J. H. Svendsen Inflammation in the genesis and perpetuation of atrial fibrillation Eur. Heart J., October 2, 2005; 26(20): 2083 - 2092. [Abstract] [Full Text] [PDF]
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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]
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Y. Rikitake, H.-H. Kim, Z. Huang, M. Seto, K. Yano, T. Asano, M. A. Moskowitz, and J. K. Liao Inhibition of Rho Kinase (ROCK) Leads to Increased Cerebral Blood Flow and Stroke Protection Stroke, October 1, 2005; 36(10): 2251 - 2257. [Abstract] [Full Text] [PDF]
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J. Hetzel, B. Balletshofer, K. Rittig, D. Walcher, W. Kratzer, V. Hombach, H.-U. Haring, W. Koenig, and N. Marx Rapid Effects of Rosiglitazone Treatment on Endothelial Function and Inflammatory Biomarkers Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1804 - 1809. [Abstract] [Full Text] [PDF]
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S. Sen-Banerjee, S. Mir, Z. Lin, A. Hamik, G. B. Atkins, H. Das, P. Banerjee, A. Kumar, and M. K. Jain Kruppel-Like Factor 2 as a Novel Mediator of Statin Effects in Endothelial Cells Circulation, August 2, 2005; 112(5): 720 - 726. [Abstract] [Full Text] [PDF]
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 K. M. Parmar, V. Nambudiri, G. Dai, H. B. Larman, M. A. Gimbrone Jr., and G. Garcia-Cardena Statins Exert Endothelial Atheroprotective Effects via the KLF2 Transcription Factor J. Biol. Chem., July 22, 2005; 280(29): 26714 - 26719. [Abstract] [Full Text] [PDF]
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 E. D. Beishuizen, J. T. Tamsma, J. W. Jukema, M. A. van de Ree, J. C. M. van der Vijver, A. E. Meinders, and M. V. Huisman The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease Diabetes Care, July 1, 2005; 28(7): 1668 - 1674. [Abstract] [Full Text] [PDF]
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R. H Boger Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials Vascular Medicine, July 1, 2005; 10(1_suppl): S19 - S25. [Abstract] [PDF]
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Y. Rikitake and J. K. Liao Rho-Kinase Mediates Hyperglycemia-Induced Plasminogen Activator Inhibitor-1 Expression in Vascular Endothelial Cells Circulation, June 21, 2005; 111(24): 3261 - 3268. [Abstract] [Full Text] [PDF]
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M. Weber, C. H. Hagedorn, D. G. Harrison, and C. D. Searles Laminar Shear Stress and 3' Polyadenylation of eNOS mRNA Circ. Res., June 10, 2005; 96(11): 1161 - 1168. [Abstract] [Full Text] [PDF]
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M. Yamakuchi, J. J.M. Greer, S. J. Cameron, K. Matsushita, C. N. Morrell, K. Talbot-Fox, W. M. Baldwin III, D. J. Lefer, and C. J. Lowenstein HMG-CoA Reductase Inhibitors Inhibit Endothelial Exocytosis and Decrease Myocardial Infarct Size Circ. Res., June 10, 2005; 96(11): 1185 - 1192. [Abstract] [Full Text] [PDF]
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N M Rajamannan, M Subramaniam, S R Stock, N J Stone, M Springett, K I Ignatiev, J P McConnell, R J Singh, R O Bonow, and T C Spelsberg Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve Heart, June 1, 2005; 91(6): 806 - 810. [Abstract] [Full Text] [PDF]
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P. Di Napoli, A. A. Taccardi, A. Grilli, M. A. De Lutiis, A. Barsotti, M. Felaco, and R. De Caterina Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts Cardiovasc Res, June 1, 2005; 66(3): 462 - 471. [Abstract] [Full Text] [PDF]
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U. Landmesser, F. Bahlmann, M. Mueller, S. Spiekermann, N. Kirchhoff, S. Schulz, C. Manes, D. Fischer, K. de Groot, D. Fliser, et al. Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans Circulation, May 10, 2005; 111(18): 2356 - 2363. [Abstract] [Full Text] [PDF]
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W. Li, T. Asagami, H. Matsushita, K.-H. Lee, and P. S. Tsao Rosuvastatin Attenuates Monocyte-Endothelial Cell Interactions and Vascular Free Radical Production in Hypercholesterolemic Mice J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 557 - 562. [Abstract] [Full Text] [PDF]
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R. H Boger Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials Vascular Medicine, May 1, 2005; 10(2_suppl): S19 - S25. [Abstract] [PDF]
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 B. Cohen, D. Singh, P. Greenland, D. M. Lloyd-Jones, A. J. Moss, B. L. Jaber, N. E. Madias, P. M Ridker, C. P. Cannon, and E. Braunwald C-Reactive Protein Levels and Outcomes after Statin Therapy N. Engl. J. Med., April 14, 2005; 352(15): 1603 - 1605. [Full Text] [PDF]
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 V. M. Campese, M. K. Nadim, and M. Epstein Are 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitors Renoprotective? J. Am. Soc. Nephrol., March 1, 2005; 16(3_suppl_1): S11 - S17. [Abstract] [Full Text] [PDF]
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A. Aicher, A. M. Zeiher, and S. Dimmeler Mobilizing Endothelial Progenitor Cells Hypertension, March 1, 2005; 45(3): 321 - 325. [Abstract] [Full Text] [PDF]
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