Published Online
on October 17, 2005

A more recent version of this article appeared on October 25, 2005

This Article Full Text (PDF) All Versions of this Article: 112/17/2708    most recent CIRCULATIONAHA.105.562041v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Deguchi, J.-O Articles by Aikawa, M. Search for Related Content PubMed PubMed Citation Articles by Deguchi, J.-O Articles by Aikawa, M. Related Collections Pathophysiology Cell biology/structural biology Genetically altered mice Acute coronary syndromes Mechanism of atherosclerosis/growth factors

Submitted on May 13, 2005
Revised on July 8, 2005
Accepted on July 20, 2005

Matrix Metalloproteinase-13/Collagenase-3 Deletion Promotes Collagen Accumulation and Organization in Mouse Atherosclerotic Plaques

Jun-O Deguchi MD, PhD, Elena Aikawa MD, PhD, Peter Libby MD, Jeffrey R. Vachon BS, Masaki Inada DDSci, PhD, Stephen M. Krane MD, Peter Whittaker PhD, and Masanori Aikawa MD, PhD^*

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (J.D., E.A., P.L., J.R.V., M.A.); Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, Mass (M.I., S.M.K.); and Departments of Emergency Medicine and Anesthesiology, University of Massachusetts Medical School, Worcester (P.W.).

^* To whom correspondence should be addressed. E-mail: maikawa{at}rics.bwh.harvard.edu.

Background--Interstitial collagen plays a crucial structural role in arteries. Matrix metalloproteinases (MMPs), including MMP-13/collagenase-3, likely contribute to collagen catabolism in atherosclerotic plaques.

Methods and Results--To test the hypothesis that a specific MMP-collagenase influences the development and structure of atherosclerotic plaques, this study used atherosclerosis-susceptible apolipoprotein E-deficient mice that lack MMP-13/collagenase-3 (Mmp-13^-/-/apoE^-/-) or express wild-type MMP-13/collagenase-3 (Mmp-13^+/+/apoE^-/-). Both groups consumed an atherogenic diet for 5 (n=8) or 10 weeks (n=9). Histological analyses of the aortic root of both groups revealed similar plaque size and accumulation of smooth muscle cells (a collagen-producing cell type) and macrophages (a major source of plaque collagenases) after 5 and 10 weeks of atherogenic diet. By 10 weeks, the plaques of Mmp-13^-/-/apoE^-/- mice contained significantly more interstitial collagen than those of Mmp-13^+/+/apoE^-/- mice (P<0.01). Furthermore, quantitative optical analyses revealed thinner and less aligned periluminal collagen fibers within the plaques of Mmp-13^+/+/apoE^-/- mice versus those from Mmp-13^-/-/apoE^-/- mice.

Conclusions--These data support the hypothesis that MMP-13/collagenase-3 plays a vital role in the regulation and organization of collagen in atherosclerotic plaques.

Key words: atherosclerosis • collagen • metalloproteinases • pathology • plaque

This article has been cited by other articles:

				R. C. Laxton, Y. Hu, J. Duchene, F. Zhang, Z. Zhang, K.-Y. Leung, Q. Xiao, R. S. Scotland, C. P. Hodgkinson, K. Smith, et al. A Role of Matrix Metalloproteinase-8 in Atherosclerosis Circ. Res., October 23, 2009; 105(9): 921 - 929. [Abstract] [Full Text] [PDF]

				J.-o Deguchi, H. Yamazaki, E. Aikawa, and M. Aikawa Chronic Hypoxia Activates the Akt and {beta}-Catenin Pathways in Human Macrophages Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1664 - 1670. [Abstract] [Full Text] [PDF]

				M. J. Frontini, C. O'Neil, C. Sawyez, B. M.C. Chan, M. W. Huff, and J. G. Pickering Lipid Incorporation Inhibits Src-Dependent Assembly of Fibronectin and Type I Collagen by Vascular Smooth Muscle Cells Circ. Res., April 10, 2009; 104(7): 832 - 841. [Abstract] [Full Text] [PDF]

				S. Ohshima, A. Petrov, S. Fujimoto, J. Zhou, M. Azure, D. S. Edwards, T. Murohara, N. Narula, S. Tsimikas, and J. Narula Molecular Imaging of Matrix Metalloproteinase Expression in Atherosclerotic Plaques of Mice Deficient in Apolipoprotein E or Low-Density-Lipoprotein Receptor J. Nucl. Med., April 1, 2009; 50(4): 612 - 617. [Abstract] [Full Text] [PDF]

				P. Libby Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis J. Lipid Res., April 1, 2009; 50(Supplement): S352 - S357. [Abstract] [Full Text] [PDF]

				E. Adiguzel, P. J Ahmad, C. Franco, and M. P Bendeck Collagens in the progression and complications of atherosclerosis Vascular Medicine, February 1, 2009; 14(1): 73 - 89. [Abstract] [PDF]

				O. Ovchinnikova, A.-K. L. Robertson, D. Wagsater, E. J. Folco, M. Hyry, J. Myllyharju, P. Eriksson, P. Libby, and G. K. Hansson T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe-/- Mice Am. J. Pathol., February 1, 2009; 174(2): 693 - 700. [Abstract] [Full Text] [PDF]

				E. A. Osborn and F. A. Jaffer The year in molecular imaging. J. Am. Coll. Cardiol. Img., January 1, 2009; 2(1): 97 - 113. [Full Text] [PDF]

				C. Tarin, M. Gomez, E. Calvo, J. A. Lopez, and C. Zaragoza Endothelial Nitric Oxide Deficiency Reduces MMP-13-Mediated Cleavage of ICAM-1 in Vascular Endothelium: A Role in Atherosclerosis Arterioscler Thromb Vasc Biol, January 1, 2009; 29(1): 27 - 32. [Abstract] [Full Text] [PDF]

				C. Franco, G. Hou, P. J. Ahmad, E. Y.K. Fu, L. Koh, W. F. Vogel, and M. P. Bendeck Discoidin Domain Receptor 1 (Ddr1) Deletion Decreases Atherosclerosis by Accelerating Matrix Accumulation and Reducing Inflammation in Low-Density Lipoprotein Receptor-Deficient Mice Circ. Res., May 23, 2008; 102(10): 1202 - 1211. [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]

				N. E. Hellman, J. Spector, J. Robinson, X. Zuo, S. Saunier, C. Antignac, J. W. Tobias, and J. H. Lipschutz Matrix Metalloproteinase 13 (MMP13) and Tissue Inhibitor of Matrix Metalloproteinase 1 (TIMP1), Regulated by the MAPK Pathway, Are Both Necessary for Madin-Darby Canine Kidney Tubulogenesis J. Biol. Chem., February 15, 2008; 283(7): 4272 - 4282. [Abstract] [Full Text] [PDF]

				J. Ohayon, O. Dubreuil, P. Tracqui, S. Le Floc'h, G. Rioufol, L. Chalabreysse, F. Thivolet, R. I. Pettigrew, and G. Finet Influence of residual stress/strain on the biomechanical stability of vulnerable coronary plaques: potential impact for evaluating the risk of plaque rupture Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1987 - H1996. [Abstract] [Full Text] [PDF]

				E. Fung, S.-M. T. Tang, J. P. Canner, K. Morishige, J. F. Arboleda-Velasquez, A. A. Cardoso, N. Carlesso, J. C. Aster, and M. Aikawa Delta-Like 4 Induces Notch Signaling in Macrophages: Implications for Inflammation Circulation, June 12, 2007; 115(23): 2948 - 2956. [Abstract] [Full Text] [PDF]

				J. A. Fallowfield, M. Mizuno, T. J. Kendall, C. M. Constandinou, R. C. Benyon, J. S. Duffield, and J. P. Iredale Scar-Associated Macrophages Are a Major Source of Hepatic Matrix Metalloproteinase-13 and Facilitate the Resolution of Murine Hepatic Fibrosis J. Immunol., April 15, 2007; 178(8): 5288 - 5295. [Abstract] [Full Text] [PDF]

				S. K. Nadkarni, M. C. Pierce, B. H. Park, J. F. de Boer, P. Whittaker, B. E. Bouma, J. E. Bressner, E. Halpern, S. L. Houser, and G. J. Tearney Measurement of Collagen and Smooth Muscle Cell Content in Atherosclerotic Plaques Using Polarization-Sensitive Optical Coherence Tomography J. Am. Coll. Cardiol., April 3, 2007; 49(13): 1474 - 1481. [Abstract] [Full Text] [PDF]

				E. Aikawa, M. Nahrendorf, D. Sosnovik, V. M. Lok, F. A. Jaffer, M. Aikawa, and R. Weissleder Multimodality Molecular Imaging Identifies Proteolytic and Osteogenic Activities in Early Aortic Valve Disease Circulation, January 23, 2007; 115(3): 377 - 386. [Abstract] [Full Text] [PDF]

				P. Libby Perplexity of Plaque Proteinases Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2181 - 2182. [Full Text] [PDF]

				J.-o Deguchi, M. Aikawa, C.-H. Tung, E. Aikawa, D.-E. Kim, V. Ntziachristos, R. Weissleder, and P. Libby Inflammation in Atherosclerosis: Visualizing Matrix Metalloproteinase Action in Macrophages In Vivo Circulation, July 4, 2006; 114(1): 55 - 62. [Abstract] [Full Text] [PDF]

				M. Kuzuya, K. Nakamura, T. Sasaki, X. Wu Cheng, S. Itohara, and A. Iguchi Effect of MMP-2 Deficiency on Atherosclerotic Lesion Formation in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1120 - 1125. [Abstract] [Full Text] [PDF]

				F. A. Jaffer, P. Libby, and R. Weissleder Molecular and Cellular Imaging of Atherosclerosis: Emerging Applications J. Am. Coll. Cardiol., April 4, 2006; 47(7): 1328 - 1338. [Abstract] [Full Text] [PDF]

				E. Aikawa, P. Whittaker, M. Farber, K. Mendelson, R. F. Padera, M. Aikawa, and F. J. Schoen Human Semilunar Cardiac Valve Remodeling by Activated Cells From Fetus to Adult: Implications for Postnatal Adaptation, Pathology, and Tissue Engineering Circulation, March 14, 2006; 113(10): 1344 - 1352. [Abstract] [Full Text] [PDF]