Published online before print August 19, 2002, doi: 10.1161/01.CIR.0000028465.52694.9B
(Circulation. 2002;106:1390.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma
From the Leducq Center for Cardiovascular Research, Department of Medicine (M.A., S.S., C.C.H., S.J.V., Y.F., P.L.) and Department of Pathology (E.R., F.J.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass, and Department of Medicine (J.L.W.), University of California, San Diego, La Jolla, Calif.
Correspondence to Masanori Aikawa, MD, PhD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Eugene Braunwald Research Center, Rm 322, Boston, MA 02115. E-mail maikawa{at}rics.bwh.harvard.edu
Background— Lipid lowering may reduce acute coronary events in patients in part by reducing vascular inflammation. Oxidative stress induces endothelial cell (EC) expression of vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemoattractant protein 1 (MCP-1) and reduces levels of atheroprotective NO, leading to monocyte recruitment and macrophage accumulation. This study tested the hypothesis that lipid lowering decreases oxidative stress and improves EC functions related to inflammatory cell accumulation.
Methods and Results— Rabbits consumed an atherogenic diet for 4 months to produce atheroma, followed by a purified chow diet for 16 months. Atherosclerotic aortas from hypercholesterolemic rabbits produced high levels of reactive oxygen species. Oxidized LDL (oxLDL) accumulated in atheroma underlying ECs that overexpress VCAM-1. In contrast, few if any ECs in atheroma stained for endothelial NO synthase (eNOS). Lipid lowering reduced reactive oxygen species production, oxLDL accumulation, and plasma levels of anti-oxLDL IgG. After lipid lowering, VCAM-1 and MCP-1 expression decreased, eNOS expression increased, and ECs exhibited a more normal ultrastructure.
Conclusions— These results establish that lipid lowering can reduce oxidative stress and EC activation in vivo. These mechanisms may contribute to improvement in endothelial function and plaque stabilization observed clinically.
Key Words: atherosclerosis • hypercholesterolemia • endothelium • cell adhesion molecules • nitric oxide synthase
This article has been cited by other articles:
 |
|
 |
|
  D. Steinberg, C. K. Glass, and J. L. Witztum Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia Circulation, August 5, 2008; 118(6): 672 - 677. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Thum and J. Borlak LOX-1 Receptor Blockade Abrogates oxLDL-induced Oxidative DNA Damage and Prevents Activation of the Transcriptional Repressor Oct-1 in Human Coronary Arterial Endothelium J. Biol. Chem., July 11, 2008; 283(28): 19456 - 19464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Choi, A. Chae, E. Miller, M. Messig, F. Ntanios, A. N. DeMaria, S. E. Nissen, J. L. Witztum, and S. Tsimikas Relationship Between Biomarkers of Oxidized Low-Density Lipoprotein, Statin Therapy, Quantitative Coronary Angiography, and Atheroma Volume Observations From the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Study. J. Am. Coll. Cardiol., July 1, 2008; 52(1): 24 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Cangemi, L. Loffredo, R. Carnevale, L. Perri, M. P. Patrizi, V. Sanguigni, P. Pignatelli, and F. Violi Early decrease of oxidative stress by atorvastatin in hypercholesterolaemic patients: effect on circulating vitamin E Eur. Heart J., January 1, 2008; 29(1): 54 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. E. Hastings, M. B. Simmers, O. G. McDonald, B. R. Wamhoff, and B. R. Blackman Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1824 - C1833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Gleissner, N. Leitinger, and K. Ley Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis Hypertension, August 1, 2007; 50(2): 276 - 283. [Full Text] [PDF]
|
|
|
|
|
|
S. Kinlay Low-Density Lipoprotein-Dependent and -Independent Effects of Cholesterol-Lowering Therapies on C-Reactive Protein: A Meta-Analysis J. Am. Coll. Cardiol., May 22, 2007; 49(20): 2003 - 2009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Chang, G. K. Sukhova, P. Libby, E. Schvartz, A. H. Lichtenstein, S. J. Field, C. Kennedy, S. Madhavarapu, J. Luo, D. Wu, et al. Deletion of the phosphoinositide 3-kinase p110{gamma} gene attenuates murine atherosclerosis PNAS, May 8, 2007; 104(19): 8077 - 8082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Rankin and A. D. Turpyn Low Carbohydrate, High Fat Diet Increases C-Reactive Protein during Weight Loss J. Am. Coll. Nutr., April 1, 2007; 26(2): 163 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsimikas, M. Aikawa, F. J. Miller Jr, E. R. Miller, M. Torzewski, S. R. Lentz, C. Bergmark, D. D. Heistad, P. Libby, and J. L. Witztum Increased Plasma Oxidized Phospholipid:Apolipoprotein B-100 Ratio With Concomitant Depletion of Oxidized Phospholipids From Atherosclerotic Lesions After Dietary Lipid-Lowering: A Potential Biomarker of Early Atherosclerosis Regression Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 175 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nahrendorf, F. A. Jaffer, K. A. Kelly, D. E. Sosnovik, E. Aikawa, P. Libby, and R. Weissleder Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis Circulation, October 3, 2006; 114(14): 1504 - 1511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kawakami, M. Aikawa, P. Alcaide, F. W. Luscinskas, P. Libby, and F. M. Sacks Apolipoprotein CIII Induces Expression of Vascular Cell Adhesion Molecule-1 in Vascular Endothelial Cells and Increases Adhesion of Monocytic Cells Circulation, August 15, 2006; 114(7): 681 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, J. T. Willerson, and P. M. Ridker C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C19 - C31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. O. Ogunshola, V. Djonov, R. Staudt, J. Vogel, and M. Gassmann Chronic excessive erythrocytosis induces endothelial activation and damage in mouse brain Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R678 - R684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
P. Avanzas, R. Arroyo-Espliguero, J. Quiles, D. Roy, and J. C. Kaski Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris Eur. Heart J., March 1, 2005; 26(5): 457 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Torzewski, P. X. Shaw, K.-R. Han, B. Shortal, K. J. Lackner, J. L. Witztum, W. Palinski, and S. Tsimikas Reduced In Vivo Aortic Uptake of Radiolabeled Oxidation-Specific Antibodies Reflects Changes in Plaque Composition Consistent With Plaque Stabilization Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2307 - 2312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Saliashvili, W. W. Davis, M. T. Harris, N.-A. Le, and W. V. Brown Simvastatin Improved Arterial Compliance in High-Risk Patients Vascular and Endovascular Surgery, November 1, 2004; 38(6): 519 - 523. [Abstract] [PDF]
|
|
|
|
|
|
S. Tsimikas, J. L. Witztum, E. R. Miller, W. J. Sasiela, M. Szarek, A. G. Olsson, G. G. Schwartz, and for the Myocardial Ischemia Reduction with Aggress High-Dose Atorvastatin Reduces Total Plasma Levels of Oxidized Phospholipids and Immune Complexes Present on Apolipoprotein B-100 in Patients With Acute Coronary Syndromes in the MIRACL Trial Circulation, September 14, 2004; 110(11): 1406 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, H. K. Lau, K.-R. Han, B. Shortal, E. R. Miller, A. Segev, L. K. Curtiss, J. L. Witztum, and B. H. Strauss Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a): Short-Term and Long-Term Immunologic Responses to Oxidized Low-Density Lipoprotein Circulation, June 29, 2004; 109(25): 3164 - 3170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Khurana, S. Shafi, J. Martin, and I. Zachary Vascular Endothelial Growth Factor Gene Transfer Inhibits Neointimal Macrophage Accumulation in Hypercholesterolemic Rabbits Arterioscler. Thromb. Vasc. Biol., June 1, 2004; 24(6): 1074 - 1080. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. L.M. Herrera, T. Didishvili, L. V. Lopez, R. H. Myers, and N. Ruiz-Opazo Genome-Wide Scan Identifies Novel QTLs for Cholesterol and LDL Levels in F2[Dahl RxS]-Intercross Rats Circ. Res., March 5, 2004; 94(4): 446 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part I: Basic Mechanisms and In Vivo Monitoring of ROS Circulation, October 21, 2003; 108(16): 1912 - 1916. [Full Text] [PDF]
|
|
|
|
|
|
W. Schaper and D. Scholz Factors Regulating Arteriogenesis Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1143 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, C. Bergmark, R. W. Beyer, R. Patel, J. Pattison, E. Miller, J. Juliano, and J. L. Witztum Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes J. Am. Coll. Cardiol., February 5, 2003; 41(3): 360 - 370. [Abstract] [Full Text] [PDF]
|
|