on March 10, 2003
Published online before print March 10, 2003, doi: 10.1161/01.CIR.0000056530.03783.81
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 15, 2002
From the Departments of Medicine and Aging (F. Cipollone, M.F., A.I., M.Z., B.P., D.D.C., F. Chiarelli, F. Cuccurullo, A.M.), Experimental and Clinical Surgery (S.U., F.S., G.B.), and Oncology and Neuroscience (R.M.), School of Medicine, and Department of Odontostomatologic Science (L.A., A.P.), School of Odontoiatry, University of Chieti G. d'Annunzio, Chieti, Italy; and Department of Experimental Medicine and Biochemical Science (R.B.), University of Rome Tor Vergata, School of Medicine, Rome, Italy. * To whom correspondence should be addressed. E-mail: mezzetti{at}unich.it.
Background--The clinical benefits of statins are attributed to changes in plaque composition that lead to reduced metalloproteinase (MMP) activity and plaque stabilization. However, the molecular mechanism of this effect is unclear. Recently, we demonstrated enhanced expression of isoforms of inducible cyclooxygenase (COX) and PGE synthase (COX-2/mPGES) in human symptomatic plaque and provided evidence that this is associated with MMP-induced plaque rupture. The aim of this study was to characterize the effect of simvastatin on inflammatory infiltration and the expression of COX-2/mPGES and MMPs in human carotid plaques. Methods and Results--Seventy patients with symptomatic carotid artery stenosis were randomized to the American Heart Association Step 1 diet plus simvastatin (40 mg/d) or the American Heart Association Step 1 diet alone for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunocytochemistry, Western blot, and reverse transcription-polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the simvastatin group had fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES and MMPs; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) collagen content; and reduced (P<0.0001) lipid and oxLDL content. Interestingly, COX-2/mPGES inhibition by simvastatin was completely reversed by mevalonate in vitro. Conclusions--This study demonstrates that simvastatin decreases inflammation and inhibits COX-2/mPGES expression in plaque macrophages, and this effect in turn may contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.
Revised on December 10, 2002
Accepted on December 12, 2002
Suppression of the Functionally Coupled Cyclooxygenase-2/Prostaglandin E Synthase as a Basis of Simvastatin-Dependent Plaque Stabilization in Humans
Francesco Cipollone MD,
Key words: hypercholesterolemia • inflammation • plaque • prostaglandins • metalloproteinases
This article has been cited by other articles:
 |
|
 |
|
  H. J. Kim, M. Y. Kim, H. Jin, H. J. Kim, S. S. Kang, H. J. Kim, J. H. Lee, K. C. Chang, J.-Y. Hwang, C. Yabe-Nishimura, et al. Peroxisome Proliferator-Activated Receptor {delta} Regulates Extracellular Matrix and Apoptosis of Vascular Smooth Muscle Cells Through the Activation of Transforming Growth Factor-{beta}1/Smad3 Circ. Res., July 2, 2009; 105(1): 16 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, M. Szarek, D. D. Waters, P. Libby, P. Ganz, and for the Myocardial Ischemia Reduction with Aggress Inflammation, Statin Therapy, and Risk of Stroke After an Acute Coronary Syndrome in the MIRACL Study Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 142 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Samuelsson, R. Morgenstern, and P.-J. Jakobsson Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target Pharmacol. Rev., September 1, 2007; 59(3): 207 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-G. Deng, A. J. Montero, and K. K. Wu Interferon-{gamma} Suppresses Cyclooxygenase-2 Promoter Activity by Inhibiting C-Jun and C/EBP{beta} Binding Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1752 - 1759. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Habib, I. Shamseddeen, M. S. Nasrallah, T. A. Antoun, G. Nemer, J. Bertoglio, R. Badreddine, and K. F. Badr Modulation of COX-2 expression by statins in human monocytic cells FASEB J, June 1, 2007; 21(8): 1665 - 1674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cuccurullo, A. Iezzi, M. L. Fazia, D. De Cesare, A. Di Francesco, R. Muraro, R. Bei, S. Ucchino, F. Spigonardo, F. Chiarelli, et al. Suppression of Rage as a Basis of Simvastatin-Dependent Plaque Stabilization in Type 2 Diabetes Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2716 - 2723. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ye, Y. Lin, S. Atar, M.-H. Huang, J. R. Perez-Polo, B. F. Uretsky, and Y. Birnbaum Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1158 - H1169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Collard, S. C. Body, S. K. Shernan, S. Wang, D. T. Mangano, and Multicenter Study of Perioperative Ischemia (MCSPI Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery. J. Thorac. Cardiovasc. Surg., August 1, 2006; 132(2): 392 - 400. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Atar, Y. Ye, Y. Lin, S. Y. Freeberg, S. P. Nishi, S. Rosanio, M.-H. Huang, B. F. Uretsky, J. R. Perez-Polo, and Y. Birnbaum Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2 Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1960 - H1968. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pavlovic, B. Du, K. Sakamoto, K. M. F. Khan, C. Natarajan, R. M. Breyer, A. J. Dannenberg, and D. J. Falcone Targeting Prostaglandin E2 Receptors as an Alternative Strategy to Block Cyclooxygenase-2-dependent Extracellular Matrix-induced Matrix Metalloproteinase-9 Expression by Macrophages J. Biol. Chem., February 10, 2006; 281(6): 3321 - 3328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hindler, C. S. Cleeland, E. Rivera, and C. D. Collard The Role of Statins in Cancer Therapy. Oncologist, January 1, 2006; 11(3): 306 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Soumian, R Gibbs, A Davies, and C Albrecht mRNA expression of genes involved in lipid efflux and matrix degradation in occlusive and ectatic atherosclerotic disease J. Clin. Pathol., December 1, 2005; 58(12): 1255 - 1260. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Mezzetti Pharmacological modulation of plaque instability Lupus, September 1, 2005; 14(9): 769 - 772. [Abstract] [PDF]
|
|
|
|
|
|
F. Cipollone, M. L. Fazia, A. Iezzi, C. Cuccurullo, D. De Cesare, S. Ucchino, F. Spigonardo, A. Marchetti, F. Buttitta, L. Paloscia, et al. Association Between Prostaglandin E Receptor Subtype EP4 Overexpression and Unstable Phenotype in Atherosclerotic Plaques in Human Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1925 - 1931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, A. Mezzetti, M. L. Fazia, C. Cuccurullo, A. Iezzi, S. Ucchino, F. Spigonardo, M. Bucci, F. Cuccurullo, S. M. Prescott, et al. Association Between 5-Lipoxygenase Expression and Plaque Instability in Humans Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1665 - 1670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Martin-Ventura, L. M. Blanco-Colio, A. Gomez-Hernandez, B. Munoz-Garcia, M. Vega, J. Serrano, L. Ortega, G. Hernandez, J. Tunon, and J. Egido Intensive Treatment With Atorvastatin Reduces Inflammation in Mononuclear Cells and Human Atherosclerotic Lesions in One Month Stroke, August 1, 2005; 36(8): 1796 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pini, T. Grosser, J. A. Lawson, T. S. Price, M. A. Pack, and G. A. FitzGerald Prostaglandin E Synthases in Zebrafish Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 315 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Birnbaum, Y. Ye, S. Rosanio, S. Tavackoli, Z.-Y. Hu, E. R. Schwarz, and B. F. Uretsky Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury Cardiovasc Res, February 1, 2005; 65(2): 345 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Egan, M. Wang, M. B. Lucitt, A. M. Zukas, E. Pure, J. A. Lawson, and G. A. FitzGerald Cyclooxygenases, Thromboxane, and Atherosclerosis: Plaque Destabilization by Cyclooxygenase-2 Inhibition Combined With Thromboxane Receptor Antagonism Circulation, January 25, 2005; 111(3): 334 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Beloqui, J. A. Paramo, J. Orbe, A. Benito, I. Colina, A. Monasterio, and J. Diez Monocyte cyclooxygenase-2 overactivity: a new marker of subclinical atherosclerosis in asymptomatic subjects with cardiovascular risk factors? Eur. Heart J., January 2, 2005; 26(2): 153 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, M. Fazia, G. Mincione, A. Iezzi, B. Pini, C. Cuccurullo, S. Ucchino, F. Spigonardo, M. Di Nisio, F. Cuccurullo, et al. Increased Expression of Transforming Growth Factor-{beta}1 as a Stabilizing Factor in Human Atherosclerotic Plaques Stroke, October 1, 2004; 35(10): 2253 - 2257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Pan, T. Pintar, J. Anton, V.-V. Lee, W. K. Vaughn, and C. D. Collard Statins Are Associated With a Reduced Incidence of Perioperative Mortality After Coronary Artery Bypass Graft Surgery Circulation, September 14, 2004; 110(11_suppl_1): II-45 - II-49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, M. Fazia, A. Iezzi, G. Ciabattoni, B. Pini, C. Cuccurullo, S. Ucchino, F. Spigonardo, M. De Luca, C. Prontera, et al. Balance Between PGD Synthase and PGE Synthase Is a Major Determinant of Atherosclerotic Plaque Instability in Humans Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1259 - 1265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. F. Khan, L. R. Howe, and D. J. Falcone Extracellular Matrix-induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression J. Biol. Chem., May 21, 2004; 279(21): 22039 - 22046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cipollone, E. Toniato, S. Martinotti, M. Fazia, A. Iezzi, C. Cuccurullo, B. Pini, S. Ursi, G. Vitullo, M. Averna, et al. A Polymorphism in the Cyclooxygenase 2 Gene as an Inherited Protective Factor Against Myocardial Infarction and Stroke JAMA, May 12, 2004; 291(18): 2221 - 2228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, M. Fazia, A. Iezzi, B. Pini, C. Cuccurullo, M. Zucchelli, D. de Cesare, S. Ucchino, F. Spigonardo, M. De Luca, et al. Blockade of the Angiotensin II Type 1 Receptor Stabilizes Atherosclerotic Plaques in Humans by Inhibiting Prostaglandin E2-Dependent Matrix Metalloproteinase Activity Circulation, March 30, 2004; 109(12): 1482 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, B. Rocca, and C. Patrono Cyclooxygenase-2 Expression and Inhibition in Atherothrombosis Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 246 - 255. [Abstract] [Full Text]
|
|
|
|
|
|
G. J. Hankey and J. W. Eikelboom Cyclooxygenase-2 Inhibitors: Are They Really Atherothrombotic, and If Not, Why Not? Stroke, November 1, 2003; 34(11): 2736 - 2740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. B Jones, D. C Sane, and D. M Herrington Matrix metalloproteinases: A review of their structure and role in acute coronary syndrome Cardiovasc Res, October 1, 2003; 59(4): 812 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cipollone, A. Iezzi, M. Fazia, M. Zucchelli, B. Pini, C. Cuccurullo, D. De Cesare, G. De Blasis, R. Muraro, R. Bei, et al. The Receptor RAGE as a Progression Factor Amplifying Arachidonate-Dependent Inflammatory and Proteolytic Response in Human Atherosclerotic Plaques: Role of Glycemic Control Circulation, September 2, 2003; 108(9): 1070 - 1077. [Abstract] [Full Text] [PDF]
|
|