(Circulation. 1997;95:205-212.)
© 1997 American Heart Association, Inc.
Articles |
Evidence for Altered Balance Between Matrix Metalloproteinases and Their Inhibitors in Human Aortic Diseases
Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
Correspondence to Peter Libby, MD, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA 02115. E-mail plibby@bustoff.bwh.harvard.edu.
Background Although abdominal aortic aneurysms (AAAs) exhibit increased expression of matrix metalloproteinases (MMPs), the functional balance between MMPs and their tissue inhibitors (TIMPs) remains uncertain. This report compares the proteolytic activity in normal aorta, aorto-occlusive disease (AOD), and AAA by use of a novel in situ zymographic technique.
Methods and Results Infrarenal aortic specimens were obtained from 25 patients undergoing surgery for AOD or AAA and were compared with normal aortic tissue (n=7) obtained from cadavers. Immunohistochemical staining was performed for collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP-3), TIMP-1, and TIMP-2. Net proteolytic activity was determined with in situ zymography whereby aortic sections were incubated on fluorescently labeled substrate. Proteolytic activity was detected under epifluorescent examination. Compared with normal aortic tissue, AOD and AAA tissue demonstrated marked increases in MMP-1 and MMP-3 immunoreactivity, predominantly in the neointima, and modest increases in TIMP-1. MMP-2 was increased in the diseased aortas, and TIMP-2 was abundant in normal, AOD, and AAA samples. Zymography revealed proteolytic activity in AOD and AAA tissues with active digestion of casein and gelatin substrate, particularly on the luminal portion of the specimens. Normal specimens exhibited no lytic activity. Comparison of AOD and AAA specimens revealed no difference in MMP/TIMP immunoreactivity or net proteolytic activity.
Conclusions MMP expression is markedly increased in AOD and AAA samples, and an imbalance between MMPs and their inhibitors results in similar proteolytic activity. The eventual formation of aneurysmal or occlusive lesions appears not to result from an ongoing difference in the proteolytic pattern.
Key Words: aneurysm • atherosclerosis • collagen • metalloproteinases • aorta
This article has been cited by other articles:
 |
|
 |
|
  W. Xiong, J. MacTaggart, R. Knispel, J. Worth, Y. Persidsky, and B. T. Baxter Blocking TNF-{alpha} Attenuates Aneurysm Formation in a Murine Model J. Immunol., August 15, 2009; 183(4): 2741 - 2746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. I. Paraskevas Applications of statins in cardiothoracic surgery: more than just lipid-lowering Eur. J. Cardiothorac. Surg., March 1, 2008; 33(3): 377 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Deguara, K. G. Burnand, J. Berg, P. Green, C. M. Lewis, G. Chinien, M. Waltham, P. Taylor, R. F. Stern, E. Solomon, et al. An increased frequency of the 5A allele in the promoter region of the MMP3 gene is associated with abdominal aortic aneurysms Hum. Mol. Genet., December 15, 2007; 16(24): 3002 - 3007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Gogly, A. Naveau, B. Fournier, N. Reinald, E. Durand, C. Brasselet, B. Coulomb, and A. Lafont Preservation of Rabbit Aorta Elastin From Degradation by Gingival Fibroblasts in an Ex Vivo Model Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1984 - 1990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Aoki, H. Kataoka, T. Moriwaki, K. Nozaki, and N. Hashimoto Role of TIMP-1 and TIMP-2 in the Progression of Cerebral Aneurysms Stroke, August 1, 2007; 38(8): 2337 - 2345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. N. Mitchell and P. Libby Vascular Remodeling in Transplant Vasculopathy Circ. Res., April 13, 2007; 100(7): 967 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Thomas, D. Gavrila, M. L. McCormick, F. J. Miller Jr, A. Daugherty, L. A. Cassis, K. C. Dellsperger, and N. L. Weintraub Deletion of p47phox Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apolipoprotein E-Deficient Mice Circulation, August 1, 2006; 114(5): 404 - 413. [Abstract] [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]
|
|
|
|
|
|
K. Shimizu, R. N. Mitchell, and P. Libby Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 987 - 994. [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]
|
|
|
|
 |
|
 W. B. Keeling, P. A. Armstrong, P. A. Stone, D. F. Bandyk, and M. L. Shames An Overview of Matrix Metalloproteinases in the Pathogenesis and Treatment of Abdominal Aortic Aneurysms Vascular and Endovascular Surgery, November 1, 2005; 39(6): 457 - 464. [Abstract] [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]
|
|
|
|
|
|
J. S. Ikonomidis, W. C. Gibson, J. E. Butler, D. M. McClister, S. E. Sweterlitsch, R. P. Thompson, R. Mukherjee, and F. G. Spinale Effects of Deletion of the Tissue Inhibitor of Matrix Metalloproteinases-1 Gene on the Progression of Murine Thoracic Aortic Aneurysms Circulation, September 14, 2004; 110(11_suppl_1): II-268 - II-273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Frederiks and O. R.F. Mook Metabolic Mapping of Proteinase Activity with Emphasis on In Situ Zymography of Gelatinases: Review and Protocols J. Histochem. Cytochem., June 1, 2004; 52(6): 711 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Creager, D. W. Jones, J. D. Easton, J. L. Halperin, A. T. Hirsch, A. H. Matsumoto, P. T. O'Gara, R. D. Safian, G. L. Schwartz, and J. A. Spittell Atherosclerotic Vascular Disease Conference: Writing Group V: Medical Decision Making and Therapy Circulation, June 1, 2004; 109(21): 2634 - 2642. [Full Text] [PDF]
|
|
|
|
 |
|
 B.A. Kelly, B.C. Bond, and L. Poston Aortic adaptation to pregnancy: elevated expression of matrix metalloproteinases-2 and -3 in rat gestation Mol. Hum. Reprod., May 1, 2004; 10(5): 331 - 337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nakashima, M. Aoki, T. Miyake, T. Kawasaki, M. Iwai, N. Jo, M. Oishi, K. Kataoka, S. Ohgi, T. Ogihara, et al. Inhibition of Experimental Abdominal Aortic Aneurysm in the Rat by Use of Decoy Oligodeoxynucleotides Suppressing Activity of Nuclear Factor {kappa}B and ets Transcription Factors Circulation, January 6, 2004; 109(1): 132 - 138. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yamazaki, J.-D. Lee, H. Shimizu, H. Uzui, and T. Ueda Circulating matrix metalloproteinase-2 is elevated in patients with congestive heart failure Eur J Heart Fail, January 1, 2004; 6(1): 41 - 45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Krex, H. Rohl, I. R. Konig, A. Ziegler, H. K. Schackert, and G. Schackert Tissue Inhibitor of Metalloproteinases-1, -2, and -3 Polymorphisms in a White Population With Intracranial Aneurysms Stroke, December 1, 2003; 34(12): 2817 - 2821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Giusti, M. C. Porciani, T. Brunelli, L. Evangelisti, S. Fedi, G. F. Gensini, R. Abbate, G. Sani, M. Yacoub, and G. Pepe Phenotypic variability of cardiovascular manifestations in Marfan Syndrome: Possible role of hyperhomocysteinemia and C677T MTHFR gene polymorphism Eur. Heart J., November 2, 2003; 24(22): 2038 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Dieter, T. Murtaugh, J. Black, and D. C. Russell Coronary Arteriomegaly in a Patient with Ehlers-Danlos Syndrome and Multiple Aneurysms: A Case Report Angiology, November 1, 2003; 54(6): 733 - 736. [Abstract] [PDF]
|
|
|
|
|
|
O. D Defawe, A. Colige, C. A Lambert, C. Munaut, P. Delvenne, C. M Lapiere, R. Limet, B. V Nusgens, and N. Sakalihasan TIMP-2 and PAI-1 mRNA levels are lower in aneurysmal as compared to athero-occlusive abdominal aortas Cardiovasc Res, October 15, 2003; 60(1): 205 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ejiri, N. Inoue, T. Tsukube, T. Munezane, Y. Hino, S. Kobayashi, K.-i. Hirata, S. Kawashima, S. Imajoh-Ohmi, Y. Hayashi, et al. Oxidative stress in the pathogenesis of thoracic aortic aneurysm: Protective role of statin and angiotensin II type 1 receptor blocker Cardiovasc Res, October 1, 2003; 59(4): 988 - 996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Satta, J. Oiva, T. Salo, H. Eriksen, P. Ohtonen, F. Biancari, T. S. Juvonen, and Y. Soini Evidence for an altered balance between matrix metalloproteinase-9 and its inhibitors in calcific aortic stenosis Ann. Thorac. Surg., September 1, 2003; 76(3): 681 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Medley, B. A. Kingwell, C. D. Gatzka, P. Pillay, and T. J. Cole Matrix Metalloproteinase-3 Genotype Contributes to Age-Related Aortic Stiffening Through Modulation of Gene and Protein Expression Circ. Res., June 13, 2003; 92(11): 1254 - 1261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F.-X. Schmid, K. Bielenberg, A. Schneider, A. Haussler, A. Keyser, and D. Birnbaum Ascending aortic aneurysm associated with bicuspid and tricuspid aortic valve: involvement and clinical relevance of smooth muscle cell apoptosis and expression of cell death-initiating proteins Eur. J. Cardiothorac. Surg., April 1, 2003; 23(4): 537 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hashimoto, G. Wen, M. T. Lawton, N. J. Boudreau, A. W. Bollen, G.-Y. Yang, N. M. Barbaro, R. T. Higashida, C. F. Dowd, V. V. Halbach, et al. Abnormal Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Brain Arteriovenous Malformations * Growth and Bleeding in BAVM: Another Role for MMPs Stroke, April 1, 2003; 34(4): 925 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Axisa, I. M. Loftus, A. R. Naylor, S. Goodall, L. Jones, P. R.F. Bell, M. M. Thompson, and C. Napoli Prospective, Randomized, Double-Blind Trial Investigating the Effect of Doxycycline on Matrix Metalloproteinase Expression Within Atherosclerotic Carotid Plaques * Editorial Comment Stroke, December 1, 2002; 33(12): 2858 - 2864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Fontaine, M.-P. Jacob, X. Houard, P. Rossignol, D. Plissonnier, E. Angles-Cano, and J.-B. Michel Involvement of the Mural Thrombus as a Site of Protease Release and Activation in Human Aortic Aneurysms Am. J. Pathol., November 1, 2002; 161(5): 1701 - 1710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Pai, G. C. Curhan, C. C. Cannuscio, N. Rifai, P. M. Ridker, and E. B. Rimm Stability of Novel Plasma Markers Associated with Cardiovascular Disease: Processing within 36 Hours of Specimen Collection Clin. Chem., October 1, 2002; 48(10): 1781 - 1784. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Wang and E. G. Lakatta Altered Regulation of Matrix Metalloproteinase-2 in Aortic Remodeling During Aging Hypertension, April 1, 2002; 39(4): 865 - 873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-H. Fan and M. J. Karnovsky Increased MMP-2 Expression in Connective Tissue Growth Factor Over-expression Vascular Smooth Muscle Cells J. Biol. Chem., March 15, 2002; 277(12): 9800 - 9805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. S. Galis and J. J. Khatri Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis: The Good, the Bad, and the Ugly Circ. Res., February 22, 2002; 90(3): 251 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. J. Ferrans New Insights Into the World of Matrix Metalloproteinases Circulation, January 29, 2002; 105(4): 405 - 407. [Full Text] [PDF]
|
|
|
|
|
|
A. Ludwig, T. Berkhout, K. Moores, P. Groot, and G. Chapman Fractalkine Is Expressed by Smooth Muscle Cells in Response to IFN-{gamma} and TNF-{alpha} and Is Modulated by Metalloproteinase Activity J. Immunol., January 15, 2002; 168(2): 604 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Saito, N. Zempo, A. Yamashita, H. Takenaka, K. Fujioka, and K. Esato Matrix Metalloproteinase Expressions in Arteriosclerotic Aneurysmal Disease Vascular and Endovascular Surgery, January 1, 2002; 36(1): 1 - 7. [Abstract] [PDF]
|
|
|
|
|
|
G. S. Cherr, S. J. Motew, J. A. Travis, J. Fingerle, L. Fisher, M. Brandl, J. K. Williams, and R. L. Geary Metalloproteinase Inhibition and the Response to Angioplasty and Stenting in Atherosclerotic Primates Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 161 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-X. Wang, B. Martin-McNulty, A. D. Freay, D. A. Sukovich, M. Halks-Miller, W.-W. Li, R. Vergona, M. E. Sullivan, J. Morser, W. P. Dole, et al. Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice Am. J. Pathol., October 1, 2001; 159(4): 1455 - 1464. [Abstract] [Full Text]
|
|
|
|
|
|
G. Sangiorgi, R. D'Averio, A. Mauriello, M. Bondio, M. Pontillo, S. Castelvecchio, S. Trimarchi, V. Tolva, G. Nano, V. Rampoldi, et al. Plasma Levels of Metalloproteinases-3 and -9 as Markers of Successful Abdominal Aortic Aneurysm Exclusion After Endovascular Graft Treatment Circulation, September 18, 2001; 104 (2009): I-288 - I-295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Zhang, S. Dhillon, I. Geary, W. M. Howell, F. Iannotti, I. N.M. Day, and S. Ye Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage Stroke, September 1, 2001; 32(9): 2198 - 2202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Vaughan, M. Casey, J. He, M. Veugelers, K. Henderson, D. Guo, R. Campagna, M. J. Roman, D. M. Milewicz, R. B. Devereux, et al. Identification of a Chromosome 11q23.2-q24 Locus for Familial Aortic Aneurysm Disease, a Genetically Heterogeneous Disorder Circulation, May 22, 2001; 103(20): 2469 - 2475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Libby and R. T. Lee Matrix Matters Circulation, October 17, 2000; 102(16): 1874 - 1876. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ikeda, R. Maekawa, H. Tanaka, M. Matsumoto, Y. Takeda, Y. Tamura, R. Nemori, and T. Yoshioka Inhibition of Gelatinolytic Activity in Tumor Tissues by Synthetic Matrix Metalloproteinase Inhibitor: Application of Film in Situ Zymography Clin. Cancer Res., August 1, 2000; 6(8): 3290 - 3296. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. Pasterkamp, E. Falk, H. Woutman, and C. Borst Techniques characterizing the coronary atherosclerotic plaque: influence on clinical decision making? J. Am. Coll. Cardiol., July 1, 2000; 36(1): 13 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tachieda, H. Niinuma, A. Ohira, S. Endoh, K. Hiramori, S. Makita, and M. Nakamura Circulating Biochemical Marker Levels of Collagen Metabolism Are Abnormal in Patients with Abdominal Aortic Aneurysm Angiology, May 1, 2000; 51(5): 385 - 392. [Abstract] [PDF]
|
|
|
|
|
|
A. B. Zaltsman, S. J. George, and A. C. Newby Increased Secretion of Tissue Inhibitors of Metalloproteinases 1 and 2 From the Aortas of Cholesterol Fed Rabbits Partially Counterbalances Increased Metalloproteinase Activity Arterioscler Thromb Vasc Biol, July 1, 1999; 19(7): 1700 - 1707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Dollery, J. R. McEwan, M. Wang, Q. A. Sang, Y. E. Liu, and Y. E. Shi TIMP-4 Is Regulated by Vascular Injury in Rats Circ. Res., March 19, 1999; 84(5): 498 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Henderson, Y.-J. Geng, G. K. Sukhova, A. D. Whittemore, J. Knox, and P. Libby Death of Smooth Muscle Cells and Expression of Mediators of Apoptosis by T Lymphocytes in Human Abdominal Aortic Aneurysms Circulation, January 12, 1999; 99(1): 96 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. E. Rasmussen and J. W. Hallett JR Inflammatory Aneurysms of the Abdominal Aorta: New Perspectives in Pathogenesis and Management Perspectives in Vascular Surgery and Endovascular Therapy, January 1, 1999; 10(2): 1 - 21. [Abstract] [PDF]
|
|
|
|
|
|
V. Davis, R. Persidskaia, L. Baca-Regen, Y. Itoh, H. Nagase, Y. Persidsky, A. Ghorpade, and B. T. Baxter Matrix Metalloproteinase-2 Production and Its Binding to the Matrix Are Increased in Abdominal Aortic Aneurysms Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1625 - 1633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Todor, I. Lewis, G. Bruno, and D. Chyatte Identification of a Serum Gelatinase Associated With the Occurrence of Cerebral Aneurysms as Pro-Matrix Metalloproteinase-2 Stroke, August 1, 1998; 29(8): 1580 - 1583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Suzuki, G. Raab, M. A. Moses, C. A. Fernandez, and M. Klagsbrun Matrix Metalloproteinase-3 Releases Active Heparin-binding EGF-like Growth Factor by Cleavage at a Specific Juxtamembrane Site J. Biol. Chem., December 12, 1997; 272(50): 31730 - 31737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Juvonen, H.-M. Surcel, J. Satta, A.-M. Teppo, A. Bloigu, H. Syrjala, J. Airaksinen, M. Leinonen, P. Saikku, and T. Juvonen Elevated Circulating Levels of Inflammatory Cytokines in Patients With Abdominal Aortic Aneurysm Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 2843 - 2847. [Abstract] [Full Text]
|
|