Published online before print June 10, 2002, doi: 10.1161/01.CIR.0000022843.76104.01
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:20.)
© 2002 American Heart Association, Inc.
Brief Rapid Communication |
Simvastatin Reduces Neointimal Thickening in Low-Density Lipoprotein Receptor–Deficient Mice After Experimental Angioplasty Without Changing Plasma Lipids
From the Cardiovascular Division (Z.C., T.F., A.C.Z., R.E., C.R., D.I.S.), Brigham and Women’s Hospital, Boston, Mass; Harvard-MIT Division of Health Sciences and Technology (C.R.), Cambridge, Mass; and Merck Research Laboratories (P.A.D., S.D.W.), Rahway, NJ.
Correspondence to Daniel I. Simon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Tower 3, Boston, MA 02115. E-mail dsimon{at}rics.bwh.harvard.edu
Background— Statins exert antiinflammatory and antiproliferative actions independent of cholesterol lowering. To determine whether these actions might affect neointimal formation, we investigated the effect of simvastatin on the response to experimental angioplasty in LDL receptor–deficient (LDLR-/-) mice, a model of hypercholesterolemia in which changes in plasma lipids are not observed in response to simvastatin.
Methods and Results— Carotid artery dilation (2.5 atm) and complete endothelial denudation were performed in male C57BL/6J LDLR-/- mice treated with low-dose (2 mg/kg) or high-dose (20 mg/kg) simvastatin or vehicle subcutaneously 72 hours before and then daily after injury. After 7 and 28 days, intimal and medial sizes were measured and the intima to media area ratio (I:M) was calculated. Total plasma cholesterol and triglyceride levels were similar in simvastatin- and vehicle-treated mice. Intimal thickening and I:M were reduced significantly by low- and high-dose simvastatin compared with vehicle alone. Simvastatin treatment was associated with reduced cellular proliferation (BrdU), leukocyte accumulation (CD45), and platelet-derived growth factor–induced phosphorylation of the survival factor Akt and increased apoptosis after injury.
Conclusions— Simvastatin modulates vascular repair after injury in the absence of lipid-lowering effects. Although the mechanisms are not yet established, additional research may lead to new understanding of the actions of statins and novel therapeutic interventions for preventing restenosis.
Key Words: restenosis • statins • inflammation • apoptosis
This article has been cited by other articles:
 |
|
 |
|
  J. D. Miller, R. M. Weiss, K. M. Serrano, R. M. Brooks II, C. J. Berry, K. Zimmerman, S. G. Young, and D. D. Heistad Lowering Plasma Cholesterol Levels Halts Progression of Aortic Valve Disease in Mice Circulation, May 26, 2009; 119(20): 2693 - 2701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zadelaar, R. Kleemann, L. Verschuren, J. de Vries-Van der Weij, J. van der Hoorn, H. M. Princen, and T. Kooistra Mouse Models for Atherosclerosis and Pharmaceutical Modifiers Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1706 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Matter, L. Ma, T. von Lukowicz, P. Meier, C. Lohmann, D. Zhang, U. Kilic, E. Hofmann, S.-W. Ha, M. Hersberger, et al. Increased Balloon-Induced Inflammation, Proliferation, and Neointima Formation in Apolipoprotein E (ApoE) Knockout Mice Stroke, October 1, 2006; 37(10): 2625 - 2632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Jaschke, C. Michaelis, S. Milz, M. Vogeser, T. Mund, L. Hengst, A. Kastrati, A. Schomig, and R. Wessely Local statin therapy differentially interferes with smooth muscle and endothelial cell proliferation and reduces neointima on a drug-eluting stent platform Cardiovasc Res, December 1, 2005; 68(3): 483 - 492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Li, C. Zhang, S. Schaefer, A. Estes, and K. U. Malik ANG II-induced neointimal growth is mediated via cPLA2- and PLD2-activated Akt in balloon-injured rat carotid artery Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2592 - H2601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Campbell, W. E. Allen, C. Sawyer, B. Vanhaesebroeck, and E. R. Trimble Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways Circ. Res., August 20, 2004; 95(4): 380 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Chen, M. Sakuma, A. C. Zago, X. Zhang, C. Shi, L. Leng, Y. Mizue, R. Bucala, and D. I. Simon Evidence for a Role of Macrophage Migration Inhibitory Factor in Vascular Disease Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 709 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. V. Desouza, S. N. Murthy, J. Diez, B. Dunne, A. S. Matta, V. A. Fonseca, and D. B. McNamara Differential Effects of Peroxisome Proliferator Activator Receptor-{alpha} and {gamma} Ligands on Intimal Hyperplasia After Balloon Catheter-Induced Vascular Injury in Zucker Rats Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2003; 8(4): 297 - 305. [Abstract] [PDF]
|
|
|
|
|
|
D. J. Kereiakes Adjunctive Pharmacotherapy before Percutaneous Coronary Intervention in Non-ST-Elevation Acute Coronary Syndromes: The Role of Modulating Inflammation Circulation, October 21, 2003; 108(90161): III-22 - 27. [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]
|
|
|
|
|
|
C. Indolfi, A. Curcio, and M. Chiariello Simvastatin Reduces Neointimal Thickening After Experimental Angioplasty Circulation, January 28, 2003; 107 (3): e25 - e25. [Full Text] [PDF]
|
|