Cardiovascular Research

Cardiovascular Research 2006 69(3):595-603; doi:10.1016/j.cardiores.2005.11.026

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Copyright © 2005, European Society of Cardiology

Vascular remodeling and protease inhibition–bench to bedside

Joost P.G. Sluijter^a,b, Dominique P.V. de Kleijn^a,b and Gerard Pasterkamp^a,*

^aExperimental Cardiology Laboratory, Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Room G02-523, 3584 CX Utrecht, The Netherlands
^bInteruniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands

^* Corresponding author. Tel.: +31 30 250 7155; fax: +31 30 252 2693. Email address: g.pasterkamp{at}hli.azu.nl

Received 31 May 2005; revised 11 November 2005; accepted 20 November 2005

	Abstract

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
Physiological and pathological tissue remodeling needs an orderly degradation of the extracellular matrix. Matrix metalloproteinases (MMPs) are proteases capable of degrading different extracellular matrix components, including collagen and elastin. MMP expression is strongly enhanced in vascular pathologies such as stenosis following balloon dilation, in-stent restenosis, sustained flow changes, aneurysm formation, and atherosclerosis. Experimental studies have revealed that some biological actions of MMPs aggravate a pathological condition, whereas others may be beneficial for the patient suffering from atherosclerotic disease. Therefore, a better understanding of the biological consequence and regulation of MMP activity is critical for the design and potential application of specific MMP inhibitors in vascular disease.

In this review, we will give an overview of preclinical experimental studies using MMP inhibitors with the objective to influence vascular occlusive diseases, and we will also highlight new targets that influence MMP expression and activity and that possess potential for therapeutic interventions.

KEYWORDS Vascular remodeling; Matrix metalloproteinases (MMP); MMP inhibition; Atherosclerosis

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The orderly degradation of interstitial extracellular matrices and basement membranes is a fundamental process during tissue remodeling in both normal and pathological conditions. Matrix metalloproteinases (MMPs) are the main physiological mediators of matrix degradation [1]. MMPs, also called matrixins, are a family of zinc-dependent endopeptidases capable of degrading extracellular matrix components such as collagens, proteoglycans, elastin, laminin, fibronectin and other glycoproteins [2]. The MMP family not only plays an important role during physiological tissue remodeling (i.e. embryonic development, bone resorption, and angiogenesis), but also during pathological remodeling in diseases associated with an unbalanced turnover of their extracellular matrix (i.e. arthritis, wound healing and tumor growth). MMPs have an important role in cardiovascular diseases which include atherosclerosis, [3] restenosis, [4] dilated cardiomyopathy [5] and myocardial repair following infarction [6]. The function of MMPs is not limited to matrix degradation since they affect proteolytic shedding or activation of cell surface and extracellular matrix proteins. Therefore, MMPs modulate cell–cell and cell–matrix interactions, which in turn influence cell differentiation, migration, proliferation, and survival.

The important role of MMPs in tissue repair has inspired many researchers to investigate the effect of compounds affecting matrix turnover during tissue remodeling. This review provides an overview of experimental studies describing the effect of protease inhibition on vascular remodeling. In addition, a short overview of other pharmaceutical approaches to influence protease activity in vascular pathology will be given.

	1. Arterial remodeling

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
The process in which arteries structurally adapt in size and composition is defined as vascular remodeling. The geometrical changes in size enable arteries to adapt and heal during physiological processes, such as blood vessel growth, pregnancy and exercise. However, remodeling also determines the degree of luminal narrowing in vascular occlusive diseases, restenosis and atherosclerosis [7]. Atherosclerosis is an inflammatory disease involving, among others, production and degradation of the extracellular matrix and the accumulation of lipids in the arterial wall [8,9]. Inflammatory cells present within the atherosclerotic shoulder regions are held responsible for the focal degradation of the atherosclerotic fibrous cap, leading to plaque rupture [10] and consequently acute thrombotic occlusion of the lumen. Imaging modalities, human pathology and animal models clearly revealed that, while atheroma develops within the intimal layer, the arterial wall undergoes major reshaping and influences arterial adaptations [11–13]. The presence of macrophages and expression of MMPs have been associated with expansive enlargement in atherosclerotic disease, but also with ruptured and rupture-prone atheromatous plaques [14,15]. MMP activity is involved in atherosclerotic lesion progression and arterial remodeling, but also in arterial aneurysmal dilation and vein graft failure. In addition, MMP expression is strongly enhanced in stenosis following experimental balloon dilation and restenosis following angioplasty, which are characteristics of vascular geometrical remodeling [16]. Since MMPs are an essential component of arterial remodeling they have been considered as pharmaceutical targets for intervention in vascular occlusive diseases.

	2. Matrix metalloproteinases (MMPs)

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
MMPs are enzymes able to degrade different components of the extracellular matrix, but their functions expand beyond matrix degradation. More than 20 different members of the MMP family have been identified so far and based on sequence homology and substrate specificity, MMPs can be classified into five groups (Table 1): collagenases, stromelysins, gelatinases, membrane type, and remaining MMPs. The natural tissue inhibitors of matrix metalloproteinases (TIMPs) are a family of inhibitors, capable in regulating MMP activity. The four members have many similarities and overlapping specificities, but their biochemical properties and local expression patterns exhibit their distinctive features [18].

View this table: [in this window] [in a new window]   Table 1 The matrix metalloproteinase family

 
Endothelial cells, smooth muscle cells, fibroblasts and infiltrating inflammatory cells can produce MMPs. In non-diseased human and animal arteries, MMP-2 and TIMP-1 and -2 are constitutively produced [3,19], but due to a tight regulation between MMPs and TIMPs, enzymatic activity of MMPs is often undetectable. On the other hand, in diseased human arteries [3] and experimental models of stenosis and atherosclerosis [20,21] there was an increase in MMP expression and MMP activities were now detectable. Mechanical stretch, shear-mediated mechanisms, and oxidative stress, which are involved in cardiovascular pathologies, can stimulate MMP expression, production and activation [22–25]. These studies point to a pathogenic role for MMPs, suggesting an imbalance between MMPs and TIMPs in vascular occlusive disease.

	3. Strategies to modulate MMP actions

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
The actions of MMPs could potentially be modulated with different approaches: (1) inhibition of MMP expression and protein synthesis, (2) inhibition of MMP activation, and (3) inhibition of MMP activity (Fig. 1). Thus far, studies have focused on the use of broad-spectrum non-specific MMP inhibitors (MMPi) and by over expression of TIMPs to intervene in vascular remodeling.

View larger version (49K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 MMP actions can be influenced on different levels: (1) inhibition of MMP expression and protein synthesis, (2) inhibition of MMP activation, and (3) inhibition of MMP activity. EMMPRIN, localized on the membrane but also in a secreted from, is of interest, since it stimulates the expression of different MMPs. Increasing evidence demonstrates that MMP activation is a focalized proteolytic process localized at the cellular membrane. Therefore, the localization of RECK on the membrane makes it a potential key factor as an inhibitor of MMP activity. Because furin-like proprotein convertases can activate several MMPs, including MT1-MMP, inhibiting its activity will modulate MMP actions. The TIMPs are natural inhibitors of MMPs and they regulate MMP activity.

 

	4. Broad-spectrum MMP inhibition in vascular remodeling

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
Since protease activity is considered a stipulation for arterial remodeling, the use of broad-spectrum MMPi has been considered as a pharmaceutical approach to improve clinical outcome of vascular occlusive pathology. Extensive preclinical data are available describing the effect of MMPi on arterial remodeling, including flow-mediated remodeling, stenosis after experimental balloon dilation, in-stent restenosis, aneurysm formation, plaque vulnerability and in arteriovenous grafts.

4.1 Flow-induced remodeling
The arterial wall senses acute alterations in arterial blood flow and responds to shear stress changes by a dilatory or constrictive response [26]. If this adaptation becomes chronic then, a permanent structural adaptation of the arterial circumference will follow. The expression and activation of MMP-2, MMP-9 and membrane type 1-MMP (MT1-MMP) is increased during flow-induced arterial remodeling [27–29]. The nonselective MMPi, RS-113,456, was shown to diminish flow-mediated arterial enlargement in the rat arteriovenous fistula model [30]. Other nonselective MMPis, doxycycline and Batimastat (BB94), resulted in a reduction in vascular enlargement in the rabbit following arteriovenous fistula creation [28]. This impaired adaptive remodeling was accompanied by less fragmentation of the internal elastic membrane which is normally observed in flow mediated enlargement. It is well established that nitric oxide is released following shear stress increase and induces acute vasodilatation. However, it was demonstrated that blood flow-induced nitric oxide also participates in MMP activation suggesting a role for nitric oxide in structural vascular adaptation [28].

4.2 Stenosis after balloon dilation
The complex response to injury after balloon dilation comprises of cell migration, cell proliferation, matrix deposition and apoptosis, resulting in constrictive arterial remodeling and neointima formation. MMPi inhibitor Batimastat effectively blocks migration and proliferation of smooth muscle cells in the balloon catheter-injured rat carotid artery, [31] and support the idea that MMPs play a significant role in the regulation of intimal hyperplasia in injured arteries [32]. However, it merits careful consideration that, although MMP activity impairs smooth muscle cell migration and neointimal formation, neointimal thickening will catch up in the long term [33,34].

Intimal hyperplasia is not the major determinant of late lumen loss following balloon dilation. Constrictive remodeling, due to adventitial thickening with collagen deposition and increased cross-linking, accelerates lumen loss during injury repair. The use of Batimastat in the atherosclerotic Yucatan micropig inhibited constrictive arterial remodeling after balloon dilation whereas neointima formation was not inhibited [35]. This was confirmed by the use of the oral MMP inhibitor Marimastat [36]. Its inhibitory effect on constrictive remodeling is explained by impaired adventitial thickening due to a reduction of collagen content after balloon dilation [37]. Although this is counterintuitive, it suggests that MMPs are not only involved in matrix degradation but also influence collagen matrix formation. It was demonstrated that MMP-9 is involved in reorganization of a collagenous matrix in addition to its role in degradation [38]. Interestingly, the use of MMPi for 7 days was sufficient for long-term inhibition of constrictive remodeling, pointing to a MMP-dependent initiator of constrictive remodeling [39].

Next to the aforementioned MMPi, tetracyclines might be an useful treatment modality to influence MMP activity. Tetracyclines "act like" antibiotics by inhibiting bacterial protein synthesis, but these pluripotent drugs affect many mammalian cell functions as well, including proliferation, migration, apoptosis, and matrix remodeling. Doxycycline is an effective inhibitor of cell proliferation, migration, and MMP activity in balloon catheter denudation of the rat carotid artery [40]. The use of a chemically modified tetracycline, lacking antibiotic activity, confirmed that this effect was due to persistent MMP inhibition. Although the use of MMPi to influence constrictive remodeling following angioplasty seemed promising, clinical trials have not been undertaken possibly due to the upcoming use of the stent.

4.3 In-stent stenosis
Stenting causes a more vigorous matrix accumulation and MMP response than angioplasty [41]. MMPi might block in-stent intimal hyperplasia and offers a novel approach to prevent in-stent stenosis. In a double-injury rabbit model, MMPi (GM6001) significantly inhibited intimal hyperplasia and intimal collagen content [42]. In our laboratory, we confirmed these observations: Marimastat significantly inhibited in-stent intimal hyperplasia by 38% in the Yucatan minipig [43]. However, results on the effects of MMPi on in-stent stenosis have been conflicting, since Batimastat did not significantly influence the degree of intimal thickening following stenting of atherosclerotic porcine femoral arteries [44]. In addition, MMPi failed to prevent constrictive remodeling or intimal hyperplasia after balloon dilation and stenting in atherosclerotic primates [45]. The battle for MMPi to prevent in-stent stenosis seemed lost when the negative results of the clinical BRILLIANT-I study, using Batimastat coated stents, were reported [46].

4.4 Aneurysm formation
Aneurysm formation can be considered a pathological manifestation of outward arterial remodeling. Systemic MMP inhibition (RS132908) was found to suppress aneurysmal dilatation in the elastase-induced abdominal aortic aneurysms rat model, accompanied by preservation of aortic elastin and an enhanced profibrotic response [47]. In addition, the broad range inhibitor Batimastat reduced expansion of experimental abdominal aortic aneurysms in the rat with concomitant impairment of the inflammatory response in these arteries [48]. Treatment with MMPi (CGS27023A) did not affect atherosclerotic lesion progression in low-density lipoprotein (LDL) receptor-deficient mice. However, medial elastin destruction, one of the features that accompanies arterial remodeling in aneurysm formation, was reduced [49]. These experimental studies demonstrated a role for MMPs in expansive arterial remodeling and the potential use of these inhibitors.

Treatment with an MMP-inhibiting tetracycline inhibited the development of experimental abdominal aortic aneurysm formation in the rat, which may be explained by selective blockade of elastolytic MMP expression in infiltrating inflammatory cells [50]. The animal models for aneurysms are mostly not atherosclerotic and chemically induced which makes extrapolation to human pathology difficult. However, reduced expression and activation of matrix metalloproteinases in the aortic wall was observed in cultured human aneurysmatic tissues from patients that received preoperative doxycycline treatment [51]. In a small patient study it was demonstrated that the aneurysm expansion after treatment with doxycycline was significantly lower compared to the placebo group [52].

4.5 Plaque vulnerability
Plaque inflammation and subsequent excretion and activation of MMPs are considered major determinants of plaque destabilization and subsequent plaque rupture. Administration of doxycycline, 2 to 8 weeks before surgery significantly reduced the concentration of MMP-1 in carotid endarterectomy plaques [53], which was confirmed in a study where patients were treated longer with doxycycline. After 6 months, there was no difference in the incidence rate of sudden death, myocardial infarction, or troponin-positive unstable angina in doxycycline compared to placebo-treated patients. However, levels of biochemical markers of inflammation, C-reactive protein (CRP), interleukin (IL)-6, and proMMP-9 activity were reduced [54]. Research on the plaque stabilizing effects of MMPi is hampered by the lack of animal models revealing atherosclerotic plaque rupture.

4.6 Arteriovenous grafts
The failure of hemodialysis access grafts in patients that undergo chronic hemodialysis is predominantly due to the rapid development of an intimal hyperplastic response in the anastomosis region between the graft and the vein. In an experimental rabbit model an increased expression of MMP-2 and -9 was observed [55]. To achieve prolonged patency rates of arteriovenous (AV) grafts in patients on hemodialysis, MMPi could be beneficial. Indeed, MMPi reduced intimal hyperplasia formation by 52% at the venous outflow tract of AV grafts in pigs, probably by inhibiting elastin degradation [56]. Interestingly, outward remodeling of the vein was not influenced by MMP inhibition as it was in arteries in aneurysm formation or during sustained increases in blood flow.

4.7 Statins and MMP inhibition
Statins are thought to exert a pleiotropic effect in atherosclerotic disease. Recent observations support the idea of the MMP inhibiting effects of statins on matrix contents and inflammation. Statins inhibit MMP secretion (MMP-1, -2, -3, -9) from rabbit, human SMCs and macrophages [57]. Moreover, statins reduce MMP expression in hyperlipidemic rabbits, [58] and increase plaque stability [59]. Statins suppress the development of experimental aneurysms in both normal and hypercholesterolemic mice, independent of lipid-lowering [60]. In primates, the use of statins, pravastatin and simvastatin, provided further support for the beneficial effect on plaque inflammation and stability [61]. Simvastatin reduced serological markers of inflammation and plasma MMP-9 activity [62]. In addition, pravastatin decreased lipids, lipid oxidation, inflammation, MMP-2, and cell death and increased TIMP-1 and collagen content in human carotid plaques, confirming its plaque-stabilizing effect in humans [63]. Interestingly, statin drug use is also associated with improved graft patency [64] but its mechanisms remain unclear.

	5. Broad-spectrum MMP inhibition in clinical studies

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
Although promising effects were observed, the use of MMPi in the clinical setting for cardiovascular pathologies was not studied. Broad-spectrum inhibition of MMPs was studied in the processes of tumor growth and metastasis, [65] but interfered with normal tissue function, such as cell-surface-receptor cleavage and release, cytokine and chemokine activation and inactivation. This leads to severe reversible side effects, like musculoskeletal pain and inflammation, and therefore, the use of a more selective MMPi is required. Since the design of the early MMPi was based on its catalytic domain and, because this domain has a high homology among MMPs, it consequently resulted in a broad-spectrum inhibition profile. Now, peptides with alternative chelators and nonpeptide compounds have been developed, and attempts are being made to identify the minimal binding requirements for MMPi to optimize the design of smaller inhibitors [66]. Preclinical research needs to unravel the role of individual MMPs in vascular disease, which is necessary to understand the pathological events and to settle if specifically inhibition of a single MMP or multiple MMPs simultaneously is necessary.

	6. Alternative interventions in MMP expression and activity

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
With the development of more specific inhibitors, antibiotics and statins that target MMP activity, a growing number of studies are focusing on different targets with the objective to manipulate MMP expression and activity. We will briefly describe some potential targets that are of interest that affect MMP actions and arterial remodeling.

6.1 Natural tissue inhibitors of matrix metalloproteinases (TIMPs)
The use of TIMPs is of greatest interest, since overexpression of TIMP-1 prevents smooth muscle cell migration [67] in vitro and in vivo and prevents neointima formation after arterial balloon injury in rats [68] and in a human vein graft models [69]. Adenovirus-mediated TIMP-2, TIMP-3 and TIMP-4 gene transfer inhibits SMC invasiveness and delays neointimal development after carotid injury or vein graft [70–72]. Moreover, the systemic delivery of the TIMP-1 gene leads to reduced neointimal formation in the injured rat carotid artery which makes it a potential protein for clinical intervention [73]. The promising inhibitory effects of TIMP-1 were enhanced by the binding of TIMP-1 protein to the human urokinase-type plasminogen activator receptor (uPAR) [74]. The urokinase-type plasminogen activator (uPA), particularly when bound to its receptor (uPAR), is thought to play a major role in local proteolytic processes, thus facilitating cell migration as may occur during angiogenesis, neointima and atherosclerotic plaque formation.

6.2 Inhibition of MMP expression
MMP expression is regulated by different cytokines and growth factors so targeting these regulatory molecules will have global inhibitory effects in many systems. One way to inhibit specific MMP expression is by RNA interference (RNAi) (Fig. 1). RNAi is the knock down of a specific gene using a complementing synthetic double stranded small interfering RNA molecule. Lakka et al. showed that co-administration of RNA targeting MMP-9 and uPAR resulted in regression of pre-established intracerebral tumor growth [75]. The feasibility of RNAi in vascular diseases was demonstrated when Fas was systemically and locally silenced resulting in a limited ischemia-reperfusion injury in mice [76].

Another potential candidate to modulate MMP expression and activity is the extracellular matrix metalloproteinase inducer (EMMPRIN)(Fig. 1). EMMPRIN was identified in human macrophage-rich atheroma, and during in vitro monocyte–macrophage differentiation [77]. EMMPRIN is a membrane-bound protein but can also be released by cells. EMMPRIN stimulates the production of different matrix MMPs, including MMP-1, MMP-2, MMP-3, and MT1-MMP [78]. How EMMPRIN regulates MMP expression and, via increased expression of MT1-MMP, activation is still unclear.

6.3 Inhibition of MMP activation
Until now, inhibition studies focused on the catalytic binding site of the MMP family, however, other regulatory proteins that are involved in the transposition into the active MMP need careful consideration. The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) regulates at least three members of the MMP family: MMP-2, MMP-9, and MT1-MMP. RECK is an important regulator of extracellular matrix remodeling and down-regulation leads to the excessive activation of MMPs (Fig. 1), thereby promoting malignant behavior of cancer cells such as invasion, metastasis, and angiogenesis [79].

Furin-like proprotein convertases are able to activate different members of the MMP family. It was recently demonstrated that furin-like proprotein convertases colocalize with MT1-MMP in macrophages, found in the atherosclerotic plaque [80]. Adventitial inhibition of furin-like proprotein convertases demonstrated their involvement in the arterial response to injury, illustrating the use of furin-like inhibitors to regulate MMP activation (Fig. 1) [81].

6.4 Other targets that affect MMP activity
Compounds other than antibiotics and statins have secondary effects on MMP activity. After experimental balloon dilation in pigs, local application of an angiotensin receptor antagonist, losartan to the site of injury, prevented formation of intima by blocking SMC proliferation. The inhibition of proliferation was accompanied by a reduction in MMP activation and cell migration [82]. In parallel, reduced gelatinolytic activity and increased collagen content were observed in plaques from patients that received an angiotensin receptor antagonist, [83] suggesting an effect on MMP regulation.

Strauss and colleagues demonstrated that the administration of elafin, a serine elastase inhibitor, may be a potential therapeutic approach to inhibit intimal hyperplasia [84]. In addition, the use of Decorin, a small proteoglycan that inhibits transforming growth factor-beta (TGF-beta) reduced intimal formation and collagen content after arterial injury [85]. TGF-beta is known to regulate endothelial cell collagen production and MMP expression [86].

Even the in-take of normal nutrients could affect MMP regulation. Regular consumption of green tea and moderate amounts of red wine is associated with reduced cardiovascular mortality. Their effects on MMP regulation have recently been demonstrated; green tea extract and red wine polyphenolic compounds inhibit smooth muscle cell invasion most likely by preventing MMP-2 expression and activation by a direct inhibition of MT1-MMP [87,88].

	7. Role of MMPs in vascular remodeling

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
Pharmaceutical experiments have provided little insight into the role of individual MMPs in vascular pathologies. Different knockout mice models verify that a single MMP can hold distinct functions within different vascular pathologies.

It is generally postulated that both MMP-2 and MMP-9 share substrates and are involved in smooth muscle cell migration [89–91]. However, the effects of MMP-2 and MMP-9 are functionally different. A deficiency in MMP-2 (–/–) reduces cell migration and inhibits neointimal formation after ligation of the mouse carotid artery, but it does not affect vessel diameter. An overexpression of MMP-9, however, does affect vessel diameter in addition to influencing cell–matrix attachment and matrix reorganization [38,92],

In general, MMPs are suggested to play an undesirable role in neointima formation and destructive capacities are bestowed on the MMPs in atherosclerotic lesions. However, the lack of MMP-9 in the atherosclerotic apolipoprotein E (ApoE)–/– mice resulted in decreased plaque areas, which contained less macrophages and collagen. However, in MMP11–/– mice, neointima formation was enhanced after electric injury of the femoral artery [93]. Also MMP3–/– ApoE–/– mice had increased plaque areas, enriched with collagen, and a decrease in lipid content, pointing to an inhibitory role in plaque progression [94]. MMP-1 transgenic mice, crossbred with ApoE–/– mice, demonstrated decreased lesions that were immature and did not display evidence of plaque rupture [95]. Surprisingly, the ApoE–/– TIMP-1–/– double-deficient mice demonstrated a reduction in atherosclerotic plaque size and a promotion in aneurysm formation, due to enhanced MMP activity [96,97]. Interestingly, aneurysm formation was prevented in the MMP3–/– ApoE–/– deficient mice, suggesting a detrimental role of MMP-3 in aneurysm formation making uniform inferences regarding vascular pathology difficult. The lack of MMP-12 and MMP-9 protected ApoE–/– mice against atherosclerotic media destruction and ectasia, mechanisms that implicate the involvement of these MMPs in aneurysm formation [98]. Interestingly, MMP-9 has an effect on lesion growth, but MMP12 deficiency does not.

These observations argue for specific roles for each MMP in different vascular pathologies. These may relate to different substrate specificities, such as growth factor activation receptor cleavage, or other cascades unrelated to matrix degradation. This is still a poorly explored area and not much research is done on this area.

	8. Concluding remarks

Top Abstract 1. Arterial remodeling 2. Matrix metalloproteinases... 3. Strategies to modulate... 4. Broad-spectrum MMP inhibition... 5. Broad-spectrum MMP inhibition... 6. Alternative interventions in... 7. Role of MMPs... 8. Concluding remarks References

 
The roles of MMPs in cardiovascular disease are diverse and broad inhibition of these proteases leads to varying success. As observed in MMP-3–/– ApoE–/– mice, lack of MMP-3 prevents aneurysm formation but will lead to atherosclerotic plaque progression illustrating that some biological actions of MMPs may aggravate a pathological condition, whereas others may be beneficial for the patient. Therefore, a better understanding of the biological consequence and regulation of MMP activity is critical for the design and potential application of more specific MMP inhibitors in vascular disease.

	Notes

 
Time for primary review 27 days

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