(Circulation. 1997;96:2115-2117.)
© 1997 American Heart Association, Inc.
Articles |
Inflammation, Metalloproteinases, and Increased Proteolysis
An Emerging Pathophysiological Paradigm in Aortic Aneurysm
From the Atherosclerosis Research Center, Division of Cardiology, and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif.
Correspondence to P.K. Shah, MD, Room 5347, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail shahp{at}csmc.edu
Key Words: Editorials • metalloproteinases
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Introduction |
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 Top Introduction References |
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Abdominal aortic aneurysm is a common and potentially lethal disease with an estimated incidence of 20 to 40 cases per 100 000 persons per year.1 In the United States, nearly 45 000 operations are performed annually for AAA.2 Most aneurysms are clinically silent until the time of rupture. Elective surgical mortality for unruptured aneurysms varies from 2% to 7%, but mortality jumps to 50% to 70% when rupture occurs before surgery.2 Risk factors for the development of AAA include advancing age, male sex, chronic obstructive lung disease, cigarette smoking, hypertension, and genetic factors.2 One of the most important determinants of risk for rupture is the size of the aneurysm.2 The overall risk of rupture is 3% to 8% for aneurysms <4 cm in diameter, whereas rupture occurs in 20% to 40% of patients with an aneurysm diameter >5 cm.2 Aneurysms between 4 and 4.5 cm in diameter carry a 10% to 12% risk of rupture.2 Although there is a considerable variability in the rate of expansion, on average, expansion occurs in an exponential fashion with an
10% diameter
increase per year (0.3 to 0.6 cm/y for aneurysms 3 to 6 cm in
size).2 Expansion rate is reduced by ß-blockers and
enhanced in patients with uncontrolled diastolic
hypertension, smoking, and chronic obstructive lung
disease.3
Recent clinical and experimental studies have challenged the
long-held notion that AAA results primarily from a complication of
atherosclerosis.4 Although intimal
pathological lesions characterize occlusive atherosclerotic aortic
disease, one of the striking hallmarks of AAA is the extensive
degeneration of the media, with evidence for extensive loss of elastin
in the media and adventitia, apoptosis and decrease in the
number of matrix-synthesizing medial smooth muscle cells, and an
adventitial and transmural inflammatory infiltrate consisting of
macrophages, lymphocytes, dendritic cells, and plasma
cells.2 5 6 7 8 9 In recent years, inflammation and excessive
extracellular matrix breakdown have been identified as the putative
processes that result in aortic expansion and aneurysm
formation.2 5 6 7 8 9 10 11 12 13 14 Initiation and expansion of AAA is
attributed to loss of elastin, normally responsible for the resilience
of the aorta, whereas loss of fibrillar collagens (types I and III),
the major source of tensile strength, is believed to ultimately result
in rupture.2 11 Several studies have shown evidence for
increased collagen breakdown as well as increased collagen synthesis in
AAA, consistent with increased collagen
turnover.10 11 12 Because of the extremely long half-life of
elastin (40 to 70 years), loss of elastin in adults is almost certainly
a manifestation of excessive elastolysis rather than insufficient
synthesis. The important role of elastolysis in aneurysm
formation is further supported by experimental models in which
aneurysms can be induced with infusion of elastase, which
in turn results in recruitment of inflammatory cells, with consequent
overproduction of cellular proteases.15 The
frequent coexistence of chronic obstructive lung disease, in which
there is evidence of excessive elastolysis in lungs, and AAA as well as
reduced elastin content in nonaneurysmal regions of the
aorta in patients with AAA provides indirect evidence in favor of a
pathophysiological role for excessive elastolysis
in AAA.2 Several recent studies have shown that AAA
tissue, compared with normal aortic tissue, contains an excess of an
arsenal of proteases, particularly members of the zinc- and
calcium-requiring matrix-degrading neutral MMP family that have the
capacity to degrade virtually all components of the extracellular
matrix in the arterial wall.7 13 14 MMP-1
(interstitial collagenase) specifically cleaves
fibrillar collagens I and III; MMP-3 (stromelysin) cleaves
proteoglycans, laminin, fibronectin, and collagen types IV, V, IX, and
X and enhances activity of MMP-1; MMP-2 (72-kD gelatinase or gelatinase
A) and MMP-9 (92-kD gelatinase or gelatinase B) both cleave denatured
collagen, collagen types IV, V, VII, and X, and elastin; MMP-7
(matrilysin) cleaves gelatin, laminin, fibronectin, collagen type IV,
versican, and elastin; and MMP-12 (macrophage
metalloelastase) degrades elastin and other
substrates.13 14 The MMPs play an important role in matrix
remodeling in various tissues, including the normal and atherosclerotic
blood vessels, in which they may be involved in plaque
disruption.16 17 The MMPs are secreted by a variety of
mesenchymal cells in a zymogen precursor form requiring extracellular
activation (by plasmin, reactive oxygen species, mast cell–derived
proteases, and membrane-type metalloproteinases) that involves removal
of an aminoterminal sequence.13 Aortic aneurysms
contain an excess of inflammatory cytokines, such as
interleukin-1ß, tumor necrosis factor-
, and interleukin-6, which
increase MMP-9 expression in macrophages, and in turn, MMPs are
involved in conversion of membrane-bound proinflammatory tumor necrosis
factor to its soluble secreted form.18 The MMPs that have
been shown to be overexpressed in the AAA tissue are primarily the
elastolytic MMPs, ie, MMP-2 and MMP-9, with some reports also
demonstrating overexpression of MMP-1 and MMP-3.2 13 14 In
addition to the MMPs, serine proteases, such as plasmin and
plasmin-generating enzymes, ie, u-PA and t-PA, and neutrophil
elastase have also been shown to be present in excess in AAA
compared with normal aortic tissue.2 13 14 Plasmin is
capable of digesting extracellular matrix directly or indirectly by
activating zymogen forms of MMP.13 Although
immunohistochemical techniques have localized these proteases to
various cell types, including smooth muscle cells in the AAA, the
predominant source, particularly for MMP-9, appears to be the
inflammatory cells, primarily monocyte-derived
macrophages.7 13 14 Several lines of evidence
support the role of MMPs derived from inflammatory cells and possibly
from smooth muscle cells in the initiation and expansion of aortic
AAA.7 13 14 These include (1) evidence for overexpression
of MMPs in AAA compared with normal aortic wall; (2) evidence for
reduced or unchanged expression of TIMPS; (3) in situ and in vitro
evidence for an increase in net matrix-degrading activity in AAA; (4)
increased expression of activators of pro-MMP, such as
plasmin and plasmin-generating enzymes such as u-PA and t-PA in AAA;
(5) experimental studies showing that infusion of elastolytic enzymes
initiates the development of AAA; and (6) demonstration that inhibition
of inflammatory cell recruitment or inhibition of MMP secretion and/or
activity by cyclooxygenase inhibitors
or by tetracycline derivatives inhibits AAA development and
expansion.19 20 21
In this issue of Circulation, McMillan et al22 have provided additional evidence in favor of the MMP-AAA expansion hypothesis. Using molecular probes, they determined the mRNA content for MMP-9 in the AAA tissue removed at surgery and related it to the diameter of the AAA measured by computerized tomography within 6 weeks before surgical removal of the AAA. The results were remarkable in that the MMP-9 mRNA content was higher in aneurysms than in normal aorta and fourfold higher in aneurysms 5 to 6.9 cm in diameter than in aneurysms 3 to 4.9 cm in diameter.22 Aneurysms >7 cm in diameter demonstrated an MMP-9 mRNA content unexpectedly lower than aneurysms 5 to 6.9 cm in diameter, although the levels were still ninefold higher than in normal aortic tissue.22 These findings are in keeping with previous findings of Firestone et al,7 who demonstrated that a higher density of inflammatory cells in the outer aortic wall was the histological feature most clearly associated with aneurysm expansion. McMillan et al thus concluded that AAA expansion is likely to result from increasing proteolysis related to increasing MMP-9 expression. Despite the elegant nature of the study and the compelling observations reported, the case for an association between MMP-9 and AAA expansion cannot be considered closed pending further clarification of several issues. First, the authors did not conduct experiments to demonstrate that in fact, increased MMP-9 mRNA expression was accompanied by an increased MMP-9 protein expression or, even more importantly, an increased net matrix-degrading activity. This is particularly important because a net increase in matrix-degrading activity would require that there be no commensurate increase in the amount or activity of TIMP-1 or other MMP inhibitors. Second, the mere existence of a relationship does not resolve the chicken-versus-egg dilemma of which is the cause (expansion or increased MMP expression) and which is the effect (expansion or increased MMP-9 expression), because increased circumferential stress associated with enlarging aneurysm (via Laplace effect) may also increase MMP expression. Third, the relative decrease in MMP-9 mRNA with AAA size >7 cm has not been satisfactorily explained.22 Because McMillan et al measured mRNA only for MMP-9, the possibility that other elastolytic proteases, such as neutrophil elastase or MMP-2, matrilysin (MMP-7), or macrophage metalloelastase (MMP-12), may play a greater role in very large aneurysms cannot be excluded. Notwithstanding these limitations, McMillan et al have provided novel quantitative data adding to the body of evidence implicating inflammatory cells and excessive proteolysis in the pathophysiology of AAA. These pathophysiological insights have potentially important therapeutic implications. For example, if proteolysis could be inhibited by the use of MMP inhibitors or specific anti-inflammatory drugs that prevent the recruitment or function of inflammatory cells, expansion of AAA may be slowed or halted, thereby diminishing the risk of rupture and perhaps the need for surgery. In this context, recent experimental studies in which anti-inflammatory molecules as well as MMP-inhibiting antibiotics, such as doxycycline and nonantibacterial, chemically modified tetracyclines, have been shown to prevent aneurysm formation or expansion are of particular interest.19 20 21
Although the pathophysiological role of inflammation and MMPs in AAA expansion is supported by a body of evidence, we know less about the processes that trigger inflammation in the aortic wall to begin with. Recently, autoantibodies against a novel 80-kD protein (a dimer of a 40-kD protein) have been identified in AAA.23 This novel protein bears sequence homology to microfibril-associated glycoprotein, which is an important component of the microfibrils that provide a structural scaffolding for tropoelastin deposition during elastogenesis. It is possible that exposure of this putative autoantigen during elastolysis may incite an immune response and trigger inflammation. Furthermore, the recent demonstration of chlamydia in AAA raises the tantalizing possibility that in some cases, infectious agents may serve to trigger an inflammatory reaction, setting off the proteolytic cascade in the aortic wall.24 An improved understanding of the molecular mechanisms involved in AAA formation and expansion is likely to yield new therapeutic strategies against this potentially lethal disease.
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Selected Abbreviations and Acronyms |
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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M. W Manning, L. A Cassis, J. Huang, S. J Szilvassy, and A. Daugherty Abdominal aortic aneurysms: fresh insights from a novel animal model of the disease Vascular Medicine, February 1, 2002; 7(1): 45 - 54. [Abstract] [PDF]
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T. W.G. Carrell, K. G. Burnand, G. M.A. Wells, J. M. Clements, and A. Smith Stromelysin-1 (Matrix Metalloproteinase-3) and Tissue Inhibitor of Metalloproteinase-3 Are Overexpressed in the Wall of Abdominal Aortic Aneurysms Circulation, January 29, 2002; 105(4): 477 - 482. [Abstract] [Full Text] [PDF]
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 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]
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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]
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 J. Lopez-Sendon Coronary reperfusion in the clinical setting: antithrombotic support to thrombolysis in the coronary care unit Eur. Heart J. Suppl., June 1, 2001; 3(suppl_C): C55 - C61. [Abstract] [PDF]
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K.G. Jones, D.J. Brull, L.C. Brown, M. Sian, R.M. Greenhalgh, S.E. Humphries, and J.T. Powell Interleukin-6 (IL-6) and the Prognosis of Abdominal Aortic Aneurysms Circulation, May 8, 2001; 103(18): 2260 - 2265. [Abstract] [Full Text] [PDF]
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K. Niwa, J. K. Perloff, S. M. Bhuta, H. Laks, D. C. Drinkwater, J. S. Child, and P. D. Miner Structural Abnormalities of Great Arterial Walls in Congenital Heart Disease : Light and Electron Microscopic Analyses Circulation, January 23, 2001; 103(3): 393 - 400. [Abstract] [Full Text] [PDF]
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D. P. Mason, R. D. Kenagy, D. Hasenstab, D. F. Bowen-Pope, R. A. Seifert, S. Coats, S. M. Hawkins, and A. W. Clowes Matrix Metalloproteinase-9 Overexpression Enhances Vascular Smooth Muscle Cell Migration and Alters Remodeling in the Injured Rat Carotid Artery Circ. Res., December 3, 1999; 85(12): 1179 - 1185. [Abstract] [Full Text] [PDF]
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L. J. Walton, I. J. Franklin, T. Bayston, L. C. Brown, R. M. Greenhalgh, G. W. Taylor, and J. T. Powell Inhibition of Prostaglandin E2 Synthesis in Abdominal Aortic Aneurysms : Implications for Smooth Muscle Cell Viability, Inflammatory Processes, and the Expansion of Abdominal Aortic Aneurysms Circulation, July 6, 1999; 100(1): 48 - 54. [Abstract] [Full Text] [PDF]
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 R.W. Thompson, S. Liao, and J.A. Curci Therapeutic Potential of Tetracycline Derivatives to Suppress the Growth of Abdominal Aortic Aneurysms Advances in Dental Research, November 1, 1998; 12(1): 159 - 165. [Abstract] [PDF]
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 A. Berton, V. Rigot, E. Huet, M. Decarme, Y. Eeckhout, L. Patthy, G. Godeau, W. Hornebeck, G. Bellon, and H. Emonard Involvement of Fibronectin Type II Repeats in the Efficient Inhibition of Gelatinases A and B by Long-chain Unsaturated Fatty Acids J. Biol. Chem., June 1, 2001; 276(23): 20458 - 20465. [Abstract] [Full Text] [PDF]
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F. J. Miller Jr, W. J. Sharp, X. Fang, L. W. Oberley, T. D. Oberley, and N. L. Weintraub Oxidative Stress in Human Abdominal Aortic Aneurysms: A Potential Mediator of Aneurysmal Remodeling Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 560 - 565. [Abstract] [Full Text] [PDF]
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