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J Am Coll Cardiol, 2006; 48:3-9, doi:10.1016/j.jacc.2006.04.098 (Published online 16 October 2006).
© 2006 by the American College of Cardiology Foundation
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STATE-OF-THE-ART PAPER

Retention and Activation of Blood-Borne Proteases in the Arterial Wall

Implications for Atherothrombosis

Xavier Houard, PhD, Anne Leclercq, Bsc, Vincent Fontaine, PhD, Michèle Coutard, PhD, Jose-Luis Martin-Ventura, PhD, Benoît Ho-Tin-Noé, PhD, Ziad Touat, Bsc, Olivier Meilhac, PhD and Jean-Baptiste Michel, MD, PhD*

Inserm Unit 698, Cardiovascular Hematology, Bio-Engineering and Remodeling, CHU Xavier Bichat, Paris, France.

Manuscript received November 29, 2005; revised manuscript received April 5, 2006, accepted April 18, 2006.

* Reprint requests and correspondence: Dr. Jean-Baptiste Michel, INSERM U698 "Cardiovascular Hematology, Bio-Engineering and Remodeling," Hôpital X. Bichat, 46, rue Henri Huchard, 75877 Paris Cedex 18, France. (Email: jbmichel{at}bichat.inserm.fr).


   Abstract
Top
 Abstract
Acquired AAA
 Intraplaque hemorrhage and...
 References
 
All forms of atheroma are characterized by a risk of arterial wall rupture leading to clinical complications. This involves medial and adventitial ruptures in abdominal aortic aneurysm (AAA) and intimal cap rupture in vulnerable atherothrombotic plaques. Extracellular proteases, including metalloproteinases, locally generated plasmin, and leukocyte elastase, are important molecular mediators of atheroma progression via their matrix degradation properties. The pathological evolution of AAA is linked to the biology of its associated mural thrombus. Indeed, in aneurysmal segments lined by a thrombus, the wall is thinner, the extracellular matrix more degraded, and the adventitial inflammatory response greater than in segments that are not. Several lines of evidence highlight the role of the thrombus, in AAA, as a reservoir of blood-borne proteases that conveys them from the lumen to the diseased wall. In stenosing atheroma, both previous and recent studies provide evidence that recurrent intraplaque hemorrhages play a dominant role in the evolution of the lesion toward vulnerability. In this review, we draw a parallel between the role of protease conveyance and activation of the mural thrombus in AAA and of intraplaque hemorrhages in stenosing atheroma. We hypothesize that intraplaque hemorrhages convey blood-borne proteases into lesions, where they are retained and activated upon thrombus/hematoma formation, thus contributing significantly to their deleterious action.

Abbreviations and Acronyms
  AAA = abdominal aortic aneurysm
  ECM = extracellular matrix
  HSP = heat shock protein
  MMP = matrix metalloproteinase
  MRI = magnetic resonance imaging
  SMC = smooth muscle cell
  t-PA = tissue-type activators

Atherothrombotic plaques evolve toward partial or total wall rupture, causing arterial thrombosis in the case of stenosing forms, and hemorrhage in the dilating aneurysmal forms. Dilatation and rupture of the arterial wall are linked to the degradation of the extracellular matrix (ECM).

The proteases involved in atherosclerotic diseases and their complications belong mainly, but not exclusively, to the matrix metalloproteinase (MMP) and serine-protease families. Among serine-proteases, plasmin and leukocyte elastase probably play a dominant role. A role for mast cell chymase (1) and cyteine-proteases cannot be excluded. Matrix metalloproteinases constitute a family of numerous zinc-dependent metalloproteinases generally secreted as pro-(inactive) forms that are activated extracellularly by several proteinases. They are produced by a variety of cell types, including, for example, mesenchymal cells (smooth muscle cells [SMCs] and fibroblasts), which constitutively secrete MMP-2 and -7 and macrophages and polymorphonuclear neutrophils in which inducible expression and/or secretion of MMP-9 occurs (2). Besides their action on fibrillar ECM, MMPs participate in pathogenic processes, by degrading other ECM constituents. Degradation of ECM not only modifies the cellular environment per se, but also generates degradation products that possess specific biological activities (matrikins) and liberates ECM-bound growth factors. Matrix metalloproteinases also directly regulate proteases and antiprotease activities (3). For example, MMP-3 can activate proMMP-9 (4), and together they cleave plasminogen and inactivate plasminogen activator inhibitor-1, {alpha}2-antiplasmin, and {alpha}1-antitrypsin (5–7).

The serine-protease plasmin is specifically activated via conversion from plasminogen, a plasma-rich zymogen synthesized by the liver, by serine-proteases, urokinase and tissue-type (t-PA) activators. Binding of plasminogen and plasmin to fibrin, to other natural polymers, or to the cell surface facilitates plasminogen activation enhances the proteolytic activity, and prevents interactions with inhibitors (6), thus focusing the in situ action of plasmin within the tissue. In contrast, the soluble form of plasmin is immediately inactivated by binding to serpins. Besides proteases, several antiproteases can also bind to tissue. {alpha}2-antiplasmin covalently binds to fibrin (8,9), and protease nexin-1 (a tissue inhibitor of thrombin and plasmin) is strongly bound to ECM (10).

Leukocyte elastase is mainly released by polymorphonuclear neutrophils (2) but has been recently shown to be also expressed and secreted by macrophages (11). The importance of neutrophils in thrombus evolution has long been recognized (12). Neutrophils are trapped at the site of fibrin formation, but more importantly, accumulate later and invade the thrombus, being 12 times more numerous in clots than in circulating blood. Neutrophils have a high affinity for the fibrin-fibronectin network (13) and bind to platelet-exposed P-selectin via the expression of PSGL-1 (14). Neutrophil activation participates in fibrinolysis via both the release of urokinase and direct actions of elastase and cathepsin G (15,16). Plasmin and elastase are involved in tissue remodeling through direct proteolysis of ECM components and, importantly, via the activation of proMMPs. An important consequence of protease activity on the ECM is the suppression of cell matrix interactions, which triggers cell apoptosis in a process called anoïkis (17). Such a phenomenon has been described for both plasmin (18) and elastase (19).

One of the main challenges concerning the understanding of atherothrombotic complications is, therefore, to determine the hierarchy of the proteases involved, to localize their sources, and to elucidate the means of their retention and activation within tissues, thus defining new diagnostic and therapeutic targets. Our recent results suggest that proteases conveyed by blood may be retained and activated by mural thrombus formation in abdominal aortic aneurysm (AAA) as well as by intraplaque hemorrhages in vulnerable plaques.


   Acquired AAA
Top
 Abstract
 Acquired AAA
Intraplaque hemorrhage and...
 References
 
Abdominal aortic aneurysm formation involves degradation of the medial layer (17), including both disappearance of SMCs by apoptosis (20) and absence of healing by cell recolonization, together with ECM degradation by proteases, adventitial angiogenic and immunoinflammatory responses, and mural thrombus formation.

The dominant role of proteases—MMPs, serine- and cysteine-proteases—in the evolution of AAAs toward enlargement and rupture is well established. Abdominal aortic aneurysms are usually characterized by the presence of a non-occlusive thrombus, through which blood flow continues, permanently maintaining interfaces between blood and thrombus at the luminal pole and thrombus and wall at the abluminal pole. The most recently formed mural thrombus/hematoma, at the luminal pole, is composed of patchy areas of red blood cells and fibrin, retaining leukocytes (mainly neutrophils), aggregated platelets, and plasma components (Fig. 1). The oldest, abluminal part is composed of a loose network of degraded fibrin, in which the specific initial components, including red blood cells and leukocytes, cannot be identified. Thus, the mural thrombus in AAA offers a unique opportunity to study the different stages of arterial thrombotic compositions and evolution within the same sample.


Figure 1
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  		Figure 1 Histologic aspect of the mural thrombus in abdominal aortic aneurysm. (A) Section through the thrombus showing the red luminal layer corresponding to a newly formed clot, associating patchy areas of red blood cells and fibrin. The intermediate layer represents a structured fibrin gel in which cellular components can no longer be recognized. The abluminal layer is composed of a loose network of degraded fibrin (hematoxylin/eosin, x10). (B) Presence of polymorphonuclear leucocytes in the luminal layer; these cells predominate in the fibrin-rich areas (hematoxylin/eosin, x60). (C) Glycoprotein IIb/IIIa immunostaining showing the predominance of platelet aggregation at the luminal pole of the thrombus in fibrin-rich areas (x10). (D) Anti-CD66b antibody stains degranulating neutrophils that accumulate in the luminal layer (x20). Inset shows neutrophils at different stages of degranulation (x100). (E) Immunostaining with anti-CD68 antibody demonstrates the paucity of monocyte/macrophages in the luminal layer of the thrombus (x20). (Inset) A macrophage that appears contracted and apoptotic (x100). (F) Matrix metalloproteinase-9 immunostaining of gelatinase granules of neutrophils present at the luminal pole of the thrombus (x100). (G) Neutrophil elastase immunostaining at the luminal pole of the thrombus colocalizes with polymorphonulear leukocytes (x100).

 
Arguments for thrombus involvement in AAA.   Several clinical observations have pointed to the involvement of the coagulation and fibrinolytic cascades in the evolution of aneurysms (21,22). Earlier, the morphologic change (crescent sign) of the mural thrombus (23) was correlated with an impending risk of rupture (24,25). Furthermore, the risk of rupture was shown to correlate with the size of the thrombus (26,27). That biological activities of the thrombus participate in aneurysmal evolution was further supported by Kazi et al. (28) who observed that the thrombus-associated aneurysmal wall was thinner and showed more frequent signs of inflammation, SMC apoptosis, and degraded ECMs as compared with adjacent blood flow-lined wall. Their findings suggested that thrombus formation may compromise the structural integrity and stability of the arterial wall (29).

Storage, activation, and release of blood-borne proteases by the mural thrombus.   The first clues to the presence of proteolytic activities in the mural thrombus came from the findings of fibrin degradation products in AAA mural thrombi (30). Comparing mural thrombus to a retracted blood clot for the presence of proteases, Gacko and Glowinski (31) and Gacko et al. (32) showed an enrichment of cathepsins, elastase, tissue factor, plasminogen, and t-PA in the former. Gelatinase activities (MMP-2 and -9) are also higher in the thrombus than in serum (33).

The mural thrombus of AAA is a complex laminated structure (30), containing several layers of thick, mixed, brown fibrin clot, underlying a red thrombus on the luminal surface (Fig. 1A). Neutrophils, platelets, and red blood cells are present in the luminal layer (34) (Figs. 1B to 1D). In contrast, monocytes/macrophages are rare (Fig. 1E). The few that are present display signs of cell death such as cell contraction, suggesting apoptosis (Fig. 1E, inset). Localization of neutrophils in the luminal part of the thrombus is associated with the detection of increased levels of MMP-8, -9, and elastase, as compared with the other layers (Figs. 1F and 1G) (35). Matrix metalloproteinase-9 is, in part, complexed to lipocalin, providing evidence for its neutrophil origin.

In an initial report, we showed that spontaneous thrombus formation and degradation in vitro was associated with the release of plasmin, responsible for clot lysis, and proMMP-9 from neutrophils trapped within the clot (36). In vivo, we next demonstrated that large amounts of plasminogen accumulate in the mural thrombus. In parallel, we showed that neutrophil-derived elastase, at the luminal pole, prevents detersion and recolonization of the thrombus by SMCs or circulating progenitors (35).

These different observations suggest that the mural thrombus, which permanently interfaces with circulating blood, is biologically active. It undergoes continuous renewal and fibrinolysis. In this concept, centrifugal conveyance of plasminogen and activators from the lumen across the thrombus play an important role in fibrinolysis (37) and MMP activation. Luminal thrombus renewal is the main determinant of neutrophil trapping and plasminogen storage, causing protease release, plasmin formation, and MMP activation, all of which contribute to the expansive arterial wall remodeling, which inexorably, sooner or later, leads to rupture. The thrombus is also probably the main source of plasma markers of AAA evolution, such as for example MMP-9 (38,39), thrombin-antithrombin, and plasmin-antiplasmin complexes (22). These observations may have clinical consequences in terms of diagnosis and therapeutics in AAA; thrombus morphology, functional imaging, and plasma biological markers could be of prognostic value.

Angiogenesis and inflammatory responses in the adventitia.   In the arterial wall, mass transport of diffusible mediators occurs unidirectionally by convection (40), due to transmural volume flow, from the lumen to the adventitia. This outward convection of mediators, from the lumen across the wall, is probably the physiological determinant of the adventitial response to arterial wall injury (41). The adventitia responds to proteolytic injury by promoting angiogenesis, resulting in the external localization of inflammation and lymphoid neogenesis (42). Fibroblast activation, mediated by inflammation, probably limits AAA evolution toward rupture through the stimulation of peripheral sclerosis. The observation of periaortic inflammation, possibly leading to the clinical entity of the "inflammatory AAA" and to retroperitoneal fibrosis (43), has focused investigations on adventitial inflammation in AAA (44,45). Therefore, in AAA, mediators generated inwardly mainly by proteolysis could be centrifugally convected toward the adventitia, where they induce angiogenic, immunoinflammatory, and fibrotic responses.


   Intraplaque hemorrhage and thrombus formation in plaque vulnerability
Top
 Abstract
 Acquired AAA
 Intraplaque hemorrhage and...
References
 
As compared with aneurysms, vulnerable stenosing plaques (Stary type V and VI lesions) are characterized by the retention of biomaterials in the core of the lesion, encapsulated between the luminal fibrous cap and the remaining media (46). The nature of this biological gruel is heterogeneous and depends on the stage of the lesion. The core includes components of different ages (unesterified lipid accumulation, frequent calcifications, macro- or microscopic hematoma) that can colocalize within the same lesion. This highlights the discontinuous evolution of the plaque, from the initial lipid retention to the formation of a more complex core, leading to plaque instability and complications (Fig. 2).


Figure 2
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  		Figure 2 Histologic aspect of culprit lesions in carotid atheroma. (A) Macroscopic aspect of a carotid culprit lesion showing the hemorrhagic nature of the core. (B) Magnetic resonance imaging of a carotid plaque hemorrhage. Intraplaque hemorrhages are characterized by a focal post-contrast enhancement in T1 spin echocardiography, giving a hyperintensity signal. (C) Masson’s trichrome staining of a culprit carotid lesion, showing the presence of: 1) neocapillaries within the lesion; and 2) intraplaque hemorrhage in the core. This example highlights the heterogeneity of culprit lesions, involving pathologies at different stages: fibrosis and hemorrhages. (D) Alizarin red staining of a culprit carotid lesion revealing the presence of calcification within the core and at the interface between the core and the media.

 
Historical background.   The proteolytic nature of the core in atheroma was first suggested by Galen (131 to 201 CE) ({alpha}{theta}{eta}{rho}{omega}µ{alpha} = atheroma = gruel). The involvement of repeated intraplaque hemorrhages in the evolution of atherosclerotic lesions toward complications was proposed as early as 1938 (47), and the importance of thrombotic material in the generation of the pultaceous core has been emphasized in pulmonary hypertension-induced plaque formation secondary to thromboembolic events (48). The crucial role of repeated intraplaque hemorrhages in the evolution of stenosing atheroma toward complications has been recently revisited by Kolodgie et al. (49). They linked unesterified cholesterol accumulation in the necrotic core of the lesion to specific red blood cell antigen expression (glycophorin). These histologic observations were corroborated by magnetic resonance imaging (MRI) of human carotid atheroma (50,51). Takaya et al. (52) demonstrated that only plaques presenting hemorrhage within the lesion, detected by MRI, showed progression over a period of 18 months, including a decrease in lumen area and an increase in core volume. Although the mechanisms leading to intraplaque hemorrhage are still not well established, numerous studies focus on the involvement of angiogenesis and the infiltration of microvessels from the adventitial vasa vasorum to invade the shoulder region of the plaque (53).

From intraplaque hemorrhage to plaque vulnerability.   Intraplaque hemorrhages convey into the lesion all the blood components, including red blood cells, leukocytes (of which 80% are neutrophils), platelets, and plasma proteins. Plasma membranes of circulating cells, including red blood cells (49), activated platelets (54,55), and probably dead leukocytes, participate in unesterified cholesterol retention within the core (Fig. 3). Platelet aggregation, prothrombin activation, and fibrinogen proteolysis all induce fibrin polymerization, which is potentially capable of trapping neutrophils and other leukocytes, and of binding plasmin and elastase (Fig. 3). In order to further explore the deleterious potential of the core contents, the release of activated proteases by carotid plaque endarterectomy specimens at different stages of evolution (type III to VI lesions of the Stary classification) were analyzed and compared with normal endarteries (mammary arteries). The greater the size and the complexity of the core, the greater was the release of activated proteases, including plasmin and the activated gelatinases MMP-2 and -9 (56). In parallel, proteolytic degradation of secreted heat shock protein (HSP) 27 occurs in diseased tissues (57). Heat shock protein 27 was previously identified using a differential proteomics approach as a very sensitive biomarker, which is decreased in plasma from atherosclerotic patients (58). Microdissection of the lesion to separate cap, core, and media demonstrated that, among these different lesion compartments, the core is the major site of plasminogen/plasmin and gelatinase storage and activation (56). Plasmin accounts for a major part of the proteolytic degradation of HSP27 (57).


Figure 3
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  		Figure 3 Representative diagram of the biological components conveyed by the intraplaque hemorrhage to the core and their roles in plaque progression. Fe = iron; MPO = myeloperoxidase; PMN = polymorphonuclear leukocyte; RBC = red blood cell.

 
Other enzymatic activities associated with the core of the atheromatous lesion have also been described, including phospholipase A2 (59) and sphingomyelinase (60), which are able to modify low-density lipoprotein particles and generate unesterified cholesterol from cell membranes. This enzymatic modification of low-density lipoprotein is a key to understanding how cholesterol retention within the arterial wall could be the driving force for the inflammatory response in atheroma (61,62). This concept of the response to lipoprotein retention could be extrapolated to apply also to the phenomenon of core retention of proteolytic activities, which may also play a crucial role in the different mechanisms of plaque progression.

The core of the lesion is a cytotoxic environment, essentially acellular, containing cell debris and only a few active macrophages (preferentially located in the cap). Detersion of cell debris by macrophages is a prerequisite for a normal healing process. This main function of macrophages is prevented in atherosclerosis, probably because they undergo apoptosis, a hallmark of human atherosclerotic lesions (63,64). Macrophage survival is dependent on adhesion (65), and proteases trigger cell apoptosis via ECM proteolysis (18,19). Proteases could thus represent central mediators of the cytotoxicity of the core. Such a function of proteases was previously proposed in AAA to explain the absence of detersion and recolonization of the mural thrombus by mesenchymatous cells (35).

The lesional core in vulnerable atheroma is, therefore, the main site of retention and activation for proteases conveyed by repeated intraplaque hemorrhages. These blood-borne proteases likely represent a major determinant for cap rupture on the luminal side, leading to occlusive thrombus, as well as for outward expansive remodeling (66). The proteolytic nature of the lesional core could thus explain the link observed between the expansive remodeling and plaque hemorrhages (67) or vulnerability (68). Therefore, the eccentric growth of the plaque and its possible rupture into the lumen, both suggest a central proteolytic role of the core in atheroma progression (69).

Conclusions.   Abdominal aortic aneurysm and atheromatous plaques are 2 clinically and etiopathogenic different forms of atherosclerosis that are characterized by the formation of a mural thrombus in the former and the recurrence of intraplaque hemorrhages in the latter. Both play a crucial role in the progression of the disease. Mural thrombus is the site of blood-borne storage and activation of proteases necessary for the proteolytic aggression of the wall. Intraplaque hemorrhages convey blood-borne proteases into the lesional core. In this review, we argue for a similar role of conveyance, storage, and activation of proteases between mural thrombus in AAA and recurrent intraplaque hemorrhages and thrombus/hematoma formation in atheromatous plaques. The concept of "proteolytic retention" within the diseased arterial wall offers new diagnostic and therapeutic targets in atheroma.


   Acknowledgments
 
The authors thank Dr. Mary Osborne-Pellegrin for editing this review and Dr. Jean-Michel Serfati for providing magnetic resonance image of plaque hemorrhage.


   Footnotes
 
Anne Leclercq was supported by the NSFA (Nouvelle Société Française d’Athérosclérose) and the FRM (Fondation pour la Recherche Médicale). Dr. Houard was supported by the Fondation Lefoulon-Delalande. These studies were supported by INSERM and the Leducq Foundation.


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 Acquired AAA
 Intraplaque hemorrhage and...
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