on November 18, 2002
Published online before print November 18, 2002, doi: 10.1161/01.CIR.0000041433.94868.12
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on July 23, 2002
From the Atherosclerosis Research Center, Division of Cardiology, Department of Medicine, and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif. * To whom correspondence should be addressed. E-mail: rajavashisth{at}cshs.org.
Background—Matrix metalloproteinases (MMPs) are thought to play a prominent role in atherogenesis and destabilization of plaque. Pericellularly localized membrane-type (MT)-MMPs activate secreted MMPs. We investigated the hypothesis that MT3-MMP is expressed in human atherosclerotic plaques and is regulated by locally produced inflammatory cytokines and oxidized low-density lipoprotein (Ox-LDL). Methods and Results—Expression and cellular localization of MT3-MMP in normal and atherosclerotic human coronary arteries were examined using specific antibodies. Abundant MT3-MMP expression was noted in medial smooth muscle cells (SMCs) of normal arteries. In atherosclerotic arteries, MT3-MMP expression was observed within complex plaques and colocalized with SMCs and macrophages (M Conclusions—MT3-MMP is expressed by SMCs and M
Revised on September 24, 2002
Accepted on September 24, 2002
Increased Expression of Membrane Type 3-Matrix Metalloproteinase in Human Atherosclerotic Plaque. Role of Activated Macrophages and Inflammatory Cytokines
Hiroyasu Uzui MD, PhD,
). Cultured human monocyte-derived M constitutively expressed MT3-MMP mRNA and proteolytically active protein, as demonstrated by mRNA analyses, immunoblotting, and gelatin zymography, respectively. Ox-LDL, tumor necrosis factor-
, or macrophage colony-stimulating factor caused dose- and time-dependent increases in steady-state levels of MT3-MMP mRNA in cultured M. This correlated with a 2- to 4-fold increase in levels of MT3-MMP immunoreactive protein and enzymatic activity in M membranes. Confocal microscopy and flow cytometry confirmed induction and spatial distribution of MT3-MMP protein from intracellular domains to the M plasma membrane by Ox-LDL, tumor necrosis factor-, or macrophage colony-stimulating factor. in human atherosclerotic plaques. Proinflammatory molecules cause a progressive increase in the expression of MT3-MMP in cultured M. Our results suggest a mechanism by which inflammatory molecules could promote M-mediated degradation of extracellular matrix and thereby contribute to plaque destabilization.
Key words: metalloproteinases • inflammation • plaque
This article has been cited by other articles:
 |
|
 |
|
  B. Dong, C. Zhang, J. B. Feng, Y. X. Zhao, S. Y. Li, Y. P. Yang, Q. L. Dong, B. P. Deng, L. Zhu, Q. T. Yu, et al. Overexpression of ACE2 Enhances Plaque Stability in a Rabbit Model of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1270 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Schneider, G. K. Sukhova, M. Aikawa, J. Canner, N. Gerdes, S.-M. T. Tang, G.-P. Shi, S. S. Apte, and P. Libby Matrix Metalloproteinase-14 Deficiency in Bone Marrow-Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques Circulation, February 19, 2008; 117(7): 931 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. K. Harris and J. D. Aplin Vascular Remodeling and Extracellular Matrix Breakdown in the Uterine Spiral Arteries During Pregnancy Reproductive Sciences, December 1, 2007; 14(8_suppl): 28 - 34. [Abstract] [PDF]
|
|
|
|
 |
|
 R. P. Sloan, P. A. Shapiro, R. E. DeMeersman, P. S. McKinley, K. J. Tracey, I. Slavov, Y. Fang, and P. D. Flood Aerobic exercise attenuates inducible TNF production in humans J Appl Physiol, September 1, 2007; 103(3): 1007 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Janssens and H. R. Lijnen What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models? Cardiovasc Res, February 15, 2006; 69(3): 585 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Newby Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates Cardiovasc Res, February 15, 2006; 69(3): 614 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Dollery and P. Libby Atherosclerosis and proteinase activation Cardiovasc Res, February 15, 2006; 69(3): 625 - 635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Peterson The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors Cardiovasc Res, February 15, 2006; 69(3): 677 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang and L. M. Wahl Synergistic enhancement of cytokine-induced human monocyte matrix metalloproteinase-1 by C-reactive protein and oxidized LDL through differential regulation of monocyte chemotactic protein-1 and prostaglandin E2 J. Leukoc. Biol., January 1, 2006; 79(1): 105 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Bengtsson, F. To, K. Hakansson, A. Grubb, L. Branen, J. Nilsson, and S. Jovinge Lack of the Cysteine Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2151 - 2156. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ikonomidis, J. Lekakis, I. Revela, F. Andreotti, and P. Nihoyannopoulos Increased circulating C-reactive protein and macrophage-colony stimulating factor are complementary predictors of long-term outcome in patients with chronic coronary artery disease Eur. Heart J., August 2, 2005; 26(16): 1618 - 1624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Stawowy, H. Meyborg, D. Stibenz, N. B. P. Stawowy, M. Roser, U. Thanabalasingam, J. P. Veinot, M. Chretien, N. G. Seidah, E. Fleck, et al. Furin-Like Proprotein Convertases Are Central Regulators of the Membrane Type Matrix Metalloproteinase-Pro-Matrix Metalloproteinase-2 Proteolytic Cascade in Atherosclerosis Circulation, May 31, 2005; 111(21): 2820 - 2827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. P. Kadoglou, S. S. Daskalopoulou, D. Perrea, and C. D. Liapis Matrix Metalloproteinases and Diabetic Vascular Complications Angiology, March 1, 2005; 56(2): 173 - 189. [Abstract] [PDF]
|
|
|
|
 |
|
 S. S. Signorelli, G. Malaponte, M. Libra, L. D. Pino, G. Celotta, V. Bevelacqua, M. Petrina, G. S Nicotra, M. Indelicato, P. M Navolanic, et al. Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease Vascular Medicine, February 1, 2005; 10(1): 1 - 6. [Abstract] [PDF]
|
|
|
|
 |
|
 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H. Gibbons, C. C. Liew, M. O. Goodarzi, J. I. Rotter, W. A. Hsueh, H. M. Siragy, R. Pratt, and V. J. Dzau Genetic Markers: Progress and Potential for Cardiovascular Disease Circulation, June 29, 2004; 109(25_suppl_1): IV-47 - IV-58. [Full Text] [PDF]
|
|
|
|
|
|
J. Cosin-Sales, M. Christiansen, P. Kaminski, C. Oxvig, M. T. Overgaard, D. Cole, D. W. Holt, and J. C. Kaski Pregnancy-Associated Plasma Protein A and Its Endogenous Inhibitor, the Proform of Eosinophil Major Basic Protein (proMBP), Are Related to Complex Stenosis Morphology in Patients With Stable Angina Pectoris Circulation, April 13, 2004; 109(14): 1724 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L S Rallidis, M G Zolindaki, P C Pentzeridis, K P Poulopoulos, A H Velissaridou, and T S Apostolou Raised concentrations of macrophage colony stimulating factor in severe unstable angina beyond the acute phase are strongly predictive of long term outcome Heart, January 1, 2004; 90(1): 25 - 29. [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]
|
|