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(Circulation. 1997;96:2115-2117.)
© 1997 American Heart Association, Inc.

Articles

Inflammation, Metalloproteinases, and Increased Proteolysis

An Emerging Pathophysiological Paradigm in Aortic Aneurysm

Prediman K. Shah, MD

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

	Introduction

Top Introduction References

 
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.

	Selected Abbreviations and Acronyms

 

AAA = abdominal aortic aneurysm MMP = matrix metalloproteinase TIMP = tissue inhibitor of metalloproteinases t-PA = tissue-type plasminogen activator u-PA = urokinase-type plasminogen activator

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

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