Matrix metalloproteinase inhibition therapy for vascular diseases

Current Prospects in Vascular Biology

Vascular Pharmacology 56 (2012) 232–244

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Vascular Pharmacology journal homepage: www.elsevier.com/locate/vph

Review

Matrix metalloproteinase inhibition therapy for vascular diseases Andrew C. Newby ⁎ Bristol Heart Institute, University of Bristol, BS2 8HW, UK

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 15 November 2011 Received in revised form 23 January 2012 Accepted 25 January 2012

The matrix metalloproteinases (MMPs) are 23 secreted or cell surface proteases that act together and with other protease classes to turn over the extracellular matrix, cleave cell surface proteins and alter the function of many secreted bioactive molecules. In the vasculature MMPs influence the migration proliferation and apoptosis of vascular smooth muscle, endothelial cells and inflammatory cells, thereby affecting intima formation, atherosclerosis and aneurysms, as substantiated in clinical and mouse knockout and transgenic studies. Prominent counterbalancing roles for MMPs in tissue destruction and repair emerge from these experiments. Naturally occurring tissue inhibitors of MMPs (TIMPs), pleiotropic mediators such as tetracyclines, chemically-synthesised small molecular weight MMP inhibitors (MMPis) and inhibitory antibodies have all shown effects in animal models of vascular disease but only doxycycline has been evaluated extensively in patients. A limitation of broad specificity MMPis is that they prevent both matrix degradation and tissue repair functions of different MMPs. Hence MMPis with more restricted specificity have been developed and recent studies in models of atherosclerosis accurately replicate the phenotypes of the corresponding gene knockouts. This review documents the established actions of MMPs and their inhibitors in vascular pathologies and considers the prospects for translating these findings into new treatments. © 2012 Elsevier Inc. All rights reserved.

Keywords: Metalloproteinase inhibitors Atherosclerosis Aneurysms Restenosis Gene therapy

Contents 1. Introduction . . . . . . . . . . . . 2. Inhibition of MMPs . . . . . . . . . 3. Intimal thickening . . . . . . . . . 4. Atherosclerosis and plaque rupture . 5. Endothelial erosions . . . . . . . . 6. Abdominal aortic aneurysms (AAAs) . 7. Conclusions . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . References . . . . . . . . . . . . . . .

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1. Introduction All resident and recruited vascular cells have the ability to remodel their surrounding extracellular matrix (ECM), in part through the action of MMPs, which are also known as matrixins (Nagase et al., 2006; Visse and Nagase, 2003). Remodelling of both structural ECM components and non-matrix substrates by MMPs affects proliferation, migration (invasion) and apoptosis of endothelial cells (ECs) (van Hinsbergh and Koolwijk, 2008), vascular smooth muscle cells (VSMCs) (Newby, 2006), leucocytes (Manicone and McGuire, 2008; ⁎ Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK. Tel.: + 44 1173423583; fax: + 44 1173423581. E-mail address: [email protected]. 1537-1891/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2012.01.007

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232 233 234 234 237 238 240 240 240

Parks et al., 2004), and several nonvascular cell types (Page-McCaw et al., 2007). The mammalian MMPs are a group of 23 structurallyrelated enzymes that have a catalytic Zn2 + ion (Nagase et al., 2006; Visse and Nagase, 2003). The MMPs have overlapping specificities for structural ECM components but can be grouped into interstitial collagenases (MMPs-1, -8, -13, -14) that cleave fibrillar collagens, gelatinases (MMPs-2 and -9) that efficiently cleave denatured collagen (i.e. gelatin) and stromelysins (MMPs-3, -7, -10, -11) that have a broad specificity but do not cleave intact fibrillar collagen. Matrix metalloelastase (MMP-12), which is more distantly related genetically to other MMPs cleaves other ECM components as well as elastin (Nagase et al., 2006; Visse and Nagase, 2003). A combination of MMPs therefore has, in principle, the ability to extensively degrade the ECM. In addition, many of the MMPs have the ability to cleave

and activate the pro-forms of other MMPs, thereby acting in protease cascades that could amplify their effectiveness (Nagase et al., 2006; Visse and Nagase, 2003). Several MMPs remain attached to the membrane (e.g. MMP-14 to -17, -25, and -26) and are therefore called membrane-type MMPs (MT-MMPs). Some soluble MMPs also have indirect cell surface attachments which, together with MT-MMPs, put them in a privileged position to degrade pericellular ECM components and act as sheddases (Nagase et al., 2006; Visse and Nagase, 2003). Indeed many MMPs have the ability to cleave cell surface proteins, modify the activity of secreted proteins and release factors sequestered in the pericellular ECM (Nagase et al., 2006; Visse and Nagase, 2003). The long list of pro-and anti-inflammatory mediators subject to modification by MMPs (Manicone and McGuire, 2008) is particularly impressive. 2. Inhibition of MMPs A cell attached inhibitor of MMP-2, MMP-9 and MMP-14 named RECK (REversion-inducing Cysteine-rich protein with Kazal motifs) is important in regulating the functions of these MMPs in cell motility and invasion (Oh et al., 2001). The mechanism by which RECK inhibits MMPs is not completely understood (Clark et al., 2007). MMPs are captured by general protease inhibitors such as α2macroglobulin. They are however most potently inhibited by 4 vertebrate tissue inhibitors of metalloproteinases (TIMPs) that can form tight complexes with MMP catalytic domains. TIMPs have a 2 domain structure, in which the N-terminal domain of TIMPs contains the inhibitory residues (Nagase et al., 2006). TIMP-3 is special in that its Cterminal domain binds tightly to the ECM, which may confine its action to the pericellular space and prolong its half-life, thereby providing a long-lived reservoir. Mutants of TIMP-3 with intact inhibitory function but free cysteines can become multimerized in the ECM. Sequestration of TIMP-3 in this way has pathological consequences in the eye, where it causes a rare form of blindness, Sorsby's Fundus Dystrophy (Li et al., 2005). TIMPs inhibit most MMPs, except that TIMP-1 only weakly inhibits MT1-MMP, MT3-MMP, MT5-MMP and MMP-19 (Nagase et al., 2006). The MMPs share very similar catalytic domains with the adamalysins (ADAMS) and the adamalysins with thrombospondin domains (ADAM-TSs). As a result, TIMP-1 and especially TIMP-3 have inhibitory actions against some of these proteases, as do most chemically-based MMP inhibitors (Nagase et al., 2006). The wider specificity of TIMP-3 may explain its unique ability to promote apoptosis of some cells (Baker et al., 1998), a property that has been employed for gene therapy (George et al., 2000, 2011). Considerable ingenuity has been employed to vary the inhibitory potency and specificity of TIMPs by mutating the critical residues (Nagase et al., 2006), which could extend their use a gene therapy reagents. TIMPs also have a variety of biological actions on cell growth, migration and apoptosis that are independent of MMP inhibition that also need to be considered in the context of gene therapy. Most importantly, TIMP-2 is an essential cofactor for pro-MMP-2 activation by MT1-MMP, the C-terminal domain of TIMP-2 acting as a binding site to assemble the activation complex (Nagase et al., 2006). In addition, TIMP-1 binds to and activates CD63, TIMP-2 binds to α3β1 integrins and TIMP-3 to VEGF receptor-2 and the angiotensin-II receptor-2, each of which interactions leads to biological functions (Stetler-Stevenson, 2008). Chelation of the active site Zn 2 + ion is the basis of action of most low molecular weight MMP inhibitors (MMPis) that have been synthesised (Hu et al., 2007). These MMPis also typically include one of several possible peptidomimetic backbones (Hu et al., 2007) and side groups that bind to one or more of six ‘subpockets’ that make up the active site cleft (Dorman et al., 2010). Recently compounds with affinity for one or more sites outside the catalytic site have been designed, to avoid the difficulties experienced with peptidomimetics and to improve the specificity for individual MMPs (Dorman et al., 2010). So far more than 50 synthetic MMPis have

233

been considered for possible clinical development and several have made it through to phase III studies, predominantly for tumour growth and metastasis or rheumatoid arthritis (Peterson, 2006). MMPis proved highly effective in pre-clinical models (Hu et al., 2007) but disappointingly none has gained regulatory approval for treating any vascular or non-vascular pathology. A common side effect, the so-called musculo-skeletal syndrome, was the bugbear of most trials with broad spectrum MMPis, which therefore had a narrow or non-existent therapeutic window (Peterson, 2006). Interestingly, TIMPs appear not to provoke these side effects (Peterson, 2006), which suggests that they arise not from inhibition of MMPs but from other metalloproteinases (ADAMs, ADAMTSs) (Hu et al., 2007) or possibly off-target effects unrelated to metalloproteinase inhibition (Peterson, 2006). The beneficial effects of MMPis were almost certainly limited by divergent actions of MMPs for example in tumour growth and metastasis (Dorman et al., 2010) or in ECM destruction and tissue repair (see below). As a result, more selective MMPis have been developed using a variety of targeting paradigms (Dorman et al., 2010). Detailed knowledge of the 3D structures of several MMP catalytic subunits allow for a clearer understanding of the specificity and for rational design. Successes include selective inhibitors of MMP-1 (Hajduk et al., 2002); MMP-2, MMP-9 and MMP-14 (Grams et al., 2001); MMP-3 (Takahashi et al., 2005); MMP8 (Agrawal et al., 2008); MMP-9 and MMP-12 (Lagente and Boichot, 2010); MMP-12 alone (Devel et al., 2006) and MMP-13 (Engel et al., 2005). Several of these MMPis have been subjected to pre-clinical and clinical applications targeted against a variety of diseases. These include proposals to use MMP-13 selective MMPi for treatment of arthritis (Clutterbuck et al., 2009), and a selective MMP-9 and MMP-12 inhibitor in lung diseases (Lagente and Boichot, 2010), including in a phase II clinical trial of chronic obstructive pulmonary disease (NCT00758459). Other examples relevant to vascular disease are detailed below. Recently, antibody inhibitors of MMPs have been added to our armamentarium and MT-MMPs proposed as favourable targets (Devy and Dransfield, 2011). As an example, an MT1-MMP (MMP-14) blocking antibody was shown to inhibit MMP-2 processing, endothelial tube formation in matrigel, and both growth and vascularisation of an MMP-14 positive tumour cell line in a xenograft model (Devy et al., 2009). Tetracyclines are a group of naturally-occurring and chemically synthesised pleiotropic agents, the action of which includes inhibition and down-regulation of MMPs (Franco et al., 2006). Doxycycline currently has regulatory approval as an adjunct to treatment of periodontitis, where its action is believed to reflect beneficial effects on ECM turnover (Sapadin and Fleischmajer, 2006). However, the biochemical mechanisms for the action of doxycycline are disappointingly unclear (Franco et al., 2006; Sapadin and Fleischmajer, 2006). Doxycycline appears to be well-tolerated in clinical trials for treatment of abdominal aortic aneurysms even though clinical efficacy remains to be demonstrated (see below) (Dodd and Spence, 2011; Golledge and Norman, 2011). Other drug classes can suppress MMP expression through antiinflammatory mechanisms. These include statins (Luan et al., 2003), which inhibit inflammatory signalling pathways by preventing prenylation of small GTPases including Rho and Rac. Nitrogencontaining bisphophonates (e.g. zoledronate) inhibit farnesyl diphosphate and therefore also prevent prenylation of small GTPases (Guenther et al., 2010). Bisphosphonates may therefore inhibit MMP production through this mechanism, although direct inhibition of the MMP catalytic Zn 2 + is also possible with some bisphophonates (Rubino et al., 2011). Agonists at several nuclear hormone receptors, notably thiazolidinediones, also exert anti-inflammatory effects by down-regulating gene transcription including that of several MMPs (Marx et al., 2003). Aspirin and other cyclooxygase inhibitors and specific inhibitors of prostaglandin E2 synthesis inhibit MMP production from monocytes (Newby, 2008), although cyclooxygenase

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independent pathways of MMP production may reduce their beneficial impact in man (Reel et al., 2011). Antagonists of specific secretagogues for MMPs (e.g. endothelin) may also be effective in reducing MMP secretion (Reel et al., 2009). 3. Intimal thickening The earliest studies of vascular MMPs and MMP inhibition therapy concerned intimal thickening following balloon angioplasty (with or without stent implantation) and vein grafting. This work was motivated by a desire to prevent intimal thickening and the resulting loss of lumen that led to restenosis after angioplasty and rapid disease progression in vein grafts. Initially, the gelatinases, MMPs-2 and -9, and later MT1-MMP, were implicated in migration and proliferation of VSMCs from expression studies in various animals and man (Newby, 2006). Induction of multiple MMPs in VSMCs by a combination of growth factors and inflammatory cytokines was identified as the key regulatory mechanism (Bond et al., 2001). MMPs were shown to act redundantly with other protease classes (e.g. cathepsins, plasminogen activators), at least for some vascular functions (Aguilera et al., 2003). Nevertheless, knockout of MMP-2 (Johnson and Galis, 2004; Kuzuya et al., 2003), MMP-9 (Cho and Reidy, 2002; Galis et al., 2002) and MMP-14 (Filippov et al., 2005) retarded intima formation in mouse models, which showed that each is indispensable. Recently, MMP-3 was also implicated thanks to its ability to activate MMP-9 (Johnson et al., 2011b). Roles for MMP-9 and MMP-12 in stimulating proliferation of human saphenous vein VSMC, mediated by cleavage of cell-surface cadherins have also been demonstrated (Dwivedi et al., 2009). Conversely, MMP-7 mediated cadherin cleavage leads apoptosis of VSMC and can therefore decrease intima formation (Williams et al., 2010). These mechanisms are summarised in Fig. 1A. Salient points are the importance of endothelial loss and dysfunction in triggering neointima formation, and the loss of basement membranes and cadherin contacts from VSMC, which allows them to migrate into the intima and proliferate. Collagen and elastin are relatively well preserved and may even be increased in the regions of stenosis. Consistent with an important role for MMPs, TIMP gene transfer was shown to inhibit intima formation in animal models of arterial injury (Cheng et al., 1998; Dollery et al., 1999; Forough et al., 1996) and human organ culture models (George et al., 1998a, 1998b, 2000). MMPis also inhibited intima formation in vitro and inhibited (Bendeck et al., 2002; Islam et al., 2003; Zempo et al., 1996) or at least delayed (Bendeck et al., 1996; Prescott et al., 1999) intimal thickening in rodent models. However, MMPis did not prevent restenosis after angioplasty or stenting in cholesterol-fed monkeys (Cherr et al., 2002) and, as reviewed by Peterson (Peterson, 2006), a small trial of MMP-inhibitor-eluting stents failed to show benefit, whereas other anti-proliferative agents were highly successful and hence became widely adopted. MMPis are still being developed to prevent vein graft intimal thickening; and other pathologies including pulmonary hypertension and transplant arterial disease might also be candidates for MMPi therapy. Given the narrow therapeutic window of broad spectrum MMPis (Peterson, 2006), there is strong case for

targeting those enzymes primarily involved in intima formation (i.e. MMP-2, MMP-3, MMP-9, MMP-12 or MMP-14). Observations that TIMPs appear to provoke fewer side effects (Peterson, 2006) may favour gene therapy approaches. Indeed TIMP-3 gene therapy, which is supported by pre-clinical studies in pigs (George et al., 2000, 2011), remains an option that is moving towards a Phase II clinical trial. 4. Atherosclerosis and plaque rupture Atherosclerosis leads over a period of many years to occlusive intimal thickening. The intima in plaques is complex; consisting of a widely varying mix of VSMCs and leucocytes, cell associated and acellular connective tissue, cell debris, extracellular lipids and calcium (See Fig. 1B). Convenient rodent models permit a sequence of steps to be identified. The earliest events appear to be deposition of low density lipoprotein (LDL) and migration of leucocytes (mainly macrophages and T-lymphocytes) under the endothelium at sites of predilection caused by disturbed flow. This leads to LDL modification and its uptake into macrophages and dendritic-like cells to generate foam cell macrophages (FCMs) (Paulson et al., 2010). ECs, VSMCs and FCMs then secrete a variety of cytokines that perpetuate the recruitment and activation of inflammatory cells (Tedgui and Mallat, 2006), which attracts modified VSMCs into the neointima (Fig. 1B). Ultimately however there is much apoptosis of VSMCs and destruction of all components of the extracellular matrix including collagen (Fig. 1B). Monocytes, macrophages and FCMs secrete a wide spectrum of MMPs and TIMPs, some constitutively and some in response to inflammatory mediators (Bar-Or et al., 2003; Newby, 2008). Inducers of MMPs come from both the innate immune system, through action on Toll-like receptors, and the acquired immune system, through actions of interferonγ (IFNγ) and a variety of interleukins (prominently IL-1, IL-4, IL-10, and IL-13) (Newby, 2008). The literature is quite extensive but also fragmentary, which has motivated recent attempts to gain a more comprehensive picture. In human monocytes, MMP-8, MMP-19, TIMP-1 and TIMP-2 are highly expressed constitutively (Bar-Or et al., 2003; Reel et al., 2011). There is clearly a group of MMPs comprising MMP-1, MMP-3, MMP-10 and MMP-14 that respond to adhesion and pro-inflammatory mediators directly through activation of MAP kinases and the NF-κB transcription factor pathway, or indirectly by action of prostaglandin E2 (Reel et al., 2011). The existence of these alternative pathways presumably reduces the effectiveness of non-steroidal anti-inflammatory agents to prevent ECM remodelling consequent upon inflammation (Reel et al., 2011). The levels of MMP-1, MMP-3 and MMP-10 decline during differentiation of monocytes to macrophages (Reel et al., 2011), which implies that recently-recruited monocytes have the potential to be highly destructive but that this tendency wanes during differentiation in the absence of continuing inflammatory activation. On the other hand MMPs-7, MMP-9 and TIMP-3 are strongly induced during macrophage differentiation by mechanisms independent of MAP kinases and NF-κB (Reel et al., 2011). Furthermore, action of inflammatory mediators (socalled ‘classical’ macrophage activators) can reactivate the production of several of these MMPs (at least MMP-1 and -3) in mature macrophages (Newby, 2008), although a complete picture is yet to

Fig. 1. Hypothetical mechanisms underlying the influence of MMPs on vascular pathologies A. Intima formation. Dysfunction or loss of endothelial cells together with trauma to VSMCs causes the release of growth factors and inflammatory cytokines that trigger MMP production. Autocrine and paracrine action of MMPs leads to disruption of cell-basement membrane interactions and cell–cell contacts mediated by cadherins, which allows VSMCs to migrate across the elastin-rich internal elastic lamina into the intima where they proliferate and synthesise fresh matrix components including collagens. B. Plaque rupture and erosion. Low density lipoprotein (LDL) deposition triggers an inflammatory response that attracts monocytes (Mo) into the intima. These take up oxidised LDL (ox-LDL) through scavenger receptors (SR) and become foam cells (FC). The inflammatory response causes release of growth factors and cytokines that mediate the production of high levels and a large spectrum of MMPs, which have the power to extensively degrade all extracellular matrix components and cause apoptosis of VSMCs. The resulting matrix may be so weakened that it ruptures. Degradation of the endothelial basement membrane may lead instead to endothelial erosion. In either case a large thrombus may ensue and block the artery, causing a myocardial infarction. C. Aneurysm formation. Initially, overproduction of MMPs from VSMCs in the medial layer causes loss of elastin. Compensatory fibrosis increases collagen content engendering a less compliant, stiff artery wall. Later on this triggers inflammation causing the ingress of macrophages that can produce larger amounts and a wider spectrum of MMPs. The end-result is extensive degradation of the extracellular matrix, leading to rapid distension and eventually rupture of the artery.

235

A Intima formation Platelets

LUMEN

Endothelium INTIMA

PDGF, IL-1 MMPs MMPs

Elastin

MMPs SMC

SMC

PDGF, IL-1

SMC

SMC

SMC

MEDIA

SMC

Collagen

Basement membranes

Cadherins

B Plaque rupture and erosion Endothelium Platelets

LUMEN

MMPs MMPs

Mo

INTIMA

FC

MMPs

MMPs SR

MMPs

ox-LDL

PDGF, IL-1 MMPs

Elastin FC SMC

MEDIA Basement membranes

Collagen

C Aneurysm formation Endothelium LUMEN SMC

INTIMA SMC

MMPs MMPs

SMC

Elastin

SMC

PDGF, IL-1 MMPs

SMC

MEDIA MF

Collagen MF

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emerge. Hence classically activated macrophages secrete a wider spectrum of MMPs than activated monocytes and therefore appear at least as destructive or maybe more so. By contrast, the current literature suggests that the alternative macrophage activator IL-4 selectively induces MMP-12 (Shimizu et al., 2004), although other MMPs and TIMPs that have not been studied yet might be similarly regulated. In atherosclerotic plaques most macrophages are FCMs, however knowledge about the MMP system in FCMs is also fragmentary and confusing, partly owing to variations in the conditions for generating FCMs in vitro. Low concentrations of oxidised lipids generate FCMs in a less inflammatory state (Kadl et al., 2010), whereas high concentrations can be pro-inflammatory and cause apoptosis. Immunocytochemistry of plaque tissues has been widely used to study FCMs in situ. Prominent staining for at least MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-11, MMP-12, MMP-13, MMP-14 and MMP-16 has been observed (Newby, 2005). Moreover, co-localisation of cleaved collagen with three collagenases (MMP-1, MMP-8 and MMP-13 (Herman et al., 2001; Sukhova et al., 1999)) suggests the enzymes are active. Recent data indicates that cells isolated from human plaques over-express MMP-1 and MMP-3 owing to activation of Toll-like receptor-2 (Monaco et al., 2009). Isolated FCMs from cholesterol-fed rabbits also over-express MMP-1, MMP-3, MMP-12 and MMP-14 (Chase et al., 2002; Johnson et al., 2008; Thomas et al., 2007). Furthermore down-regulation of TIMP-3 in a subpopulation of rabbit FCMs increases their propensity to be destructive, invasive, and proliferative, and to undergo apoptosis (Johnson et al., 2008). These experiments provide compelling evidence that classical and to a lesser extent alternative macrophage activation up-regulates MMPs. Furthermore, evidence for the presence of activated MMPs in atherosclerotic plaques and isolated FCMs suggests that MMPs are culprits in atherosclerosis formation and its adverse clinical consequences. Atherosclerosis underlies strokes and myocardial infarctions (MIs) which are the leading causes of mortality in advanced countries and are rapidly increasing in the developing world. From post-mortem studies and a limited amount of in-vivo imaging (Arbustini et al., 1999; Kubo et al., 2007) about two thirds of thirds of MIs depending on the study population result from disrupted plaque caps that expose a thrombogenic lipid core. Rupture prone plaques tend to be: large, highly inflamed, occupied by large lipid cores, and have thin fibrous caps with depleted collagens in the cap and lipid core (Virmani et al., 2006). Potential mechanisms are illustrated in

Fig. 1B. Plaque rupture appears to be the eventual consequence of the combination of a thin, weakened plaque cap, a highly flexible core and an exaggerated pressure wave during the cardiac cycle caused by hypertension and arterial stiffness. Many descriptive histological studies emphasized the location of MMPs in FCMs at the vulnerable, shoulder regions of plaques (Newby, 2005). Moreover, quantitative associations between levels of MMP-8 and MMP-9 in plaques with histological features of plaque vulnerability to rupture provide further evidence for their pathological role (Sluijter et al., 2006). Interestingly MMP-2 seems mainly to be expressed by VSMCs and therefore shows the opposite association and could be protective through the mechanisms discussed in the section on intima formation (Sluijter et al., 2006). Transgenic and knockout models have been used to investigate the role of MMPs and TIMPs in atherogenesis and the development of vulnerable plaque morphology (see Table 1). As well as plaque size, criteria of vulnerability borrowed from human pathology included fewer VSMC, more macrophages, decreased collagen content and disruption of other ECM components, in particular elastic fibres in the media at the base of plaques. Intraplaque haemorrhages and the occurrence of buried fibrous caps, which may be the signature of silent plaque ruptures, were also counted (Johnson et al., 2005a). Knocking out TIMP-1, which is likely to promote MMP activity, caused medial destruction in two studies (Lemaitre et al., 2003; Silence et al., 2002), and was associated in one study with increased macrophage content (see Table 1). Mice do not actively express MMP-1 but ApoE null mice transgenic for human MMP-1 in macrophages had smaller plaques with less collagen (Lemaitre et al., 2001) (Table 1). Over expressing a mutated form of MMP-9 that becomes fully auto-activated produced high levels of plaque instability in the same mouse model (Gough et al., 2006). Over expressing a native pro-form of MMP-9 did not affect plaque stability in arterial plaques (Gough et al., 2006) but did in advanced plaques caused by collar implantation into ApoE null mice (de Nooijer et al., 2006). Apparently the expression and activation of pro-MMPs both determine whether pathological matrix destruction takes place. When MMP knockouts were studied in the ApoE null background, both protective and deleterious effects were documented (Table 1). MMP-2 knockout reduced VSMC accumulation in plaques, suggesting impaired plaque stability (Kuzuya et al., 2006). MMP-3 knockout increased plaque size in two studies (Johnson et al., 2005b; Silence et

Table 1 Effects of MMP interventions in atherosclerotic plaque development and stability. Number

Site

Size

SMC

Macro-phages

ECM Intact?

Overall Stability

References

MMP-1 ++ MMP-2 null MMP-3 null

Root/arch Root/arch Ao, BCA

↓ ↓ ↑, ↑

= ↓ ?, ↓

= = ↓, =

↓ = ↑, ?

? ↓ ↑, ↓

MMP-7 null MMP-8 null MMP-9 null

BCA Ao Ao, BCA

= ↓ ↓, ↑

↑ = ?, ↓

= ↓ ↓, ↑

? ↑ ↓↑, =

↑ ↑ ↑, ↓

MMP-9 ++

Arch, collar

=, =

=, =

=, =

=, =

=, ↓

MMP-9 ++a MMP-12 null

Arch, BCA Ao, BCA

=, ↓

=, ↑

= =, ↓

↓ =, ?

↓ ↑, ↑

MMP-12 ++a MMP-13 null MMP-14 null TIMP-1 null

Ao (rabbit) Root LDLR null, Root Root, Aorta

↑ = = =, ↓

↑ = = =, ?

↑ = = =, ↑

? ↑ ↑ ↓, ↓

? ↓ ↓ ↓, ↓

TIMP-1 ++

Root, BCA

↓, =

?, =

↓, =

↑, ↑

↑, =

TIMP-2 ++

BCA

↓

↑

↓

↑

↑

Lemaitre et al. (2001) Kuzuya et al.(2006) Silence et al. (2001) and Johnson et al. (2005b) Johnson et al. (2005b) Laxton et al. (2009) Luttun et al. (2004) and Johnson et al. (2005b) Gough et al. (2006) and de Nooijer et al. (2006) Gough et al. (2006) Luttun et al. (2004) and Johnson et al. (2005b) Liang et al. (2006)) Deguchi et al. (2005) Schneider et al. (2008) Lemaitre et al. (2003) and Silence et al. (2002) Johnson et al. (2006a) and Rouis et al. (1999) Johnson et al. (2006a)

Results of overexpression (++), overexpression of activated enzymes (++a) and knockout (null) on the specified parameters. Unless specified data were obtained in ApoE null mice. Increases (↑), decreases (↓) or no change (=). Missing or uncertain data is indicated as (?). Abbreviations: Ao= aorta, arch= aortic arch, BCA = brachiocephalic artery, root = aortic root.

al., 2001) and decreased elastin breaks in one of these (Silence et al., 2001), implying greater stability. However, VSMC content was decreased and buried fibrous layers increased in the second, implying less stability (Johnson et al., 2005b). Reduced recruitment of VSMC was also observed into MMP-3 null plaques (Johnson et al., 2005b) and this is consistent with the impaired intima formation response in these mice (Johnson et al., 2011b). By contrast, MMP-7 deletion increased VSMC numbers in ApoE null mouse plaques (Johnson et al., 2005b), consistent with the permissive role of MMP-7 in VSMC apoptosis (Williams et al., 2010). MMP-8 knockout reduced aortic atherosclerosis and inflammation, possibly via an indirect effect on angiotensin-I processing to angiotensin-II (Laxton et al., 2009). Studies of MMP-9 knockout mice led to contradictory conclusions on plaque stability. Reduced plaque size, macrophage content and elastin breaks were found in one study (Luttun et al., 2004), but increased plaque size, macrophage content and buried fibrous layers in another (Johnson et al., 2005b) (Table 1). The ability of MMP-9 to promote intima formation mentioned above could explain the more unstable plaque phenotype seen in MMP-9 null mice in one study (Johnson et al., 2005b). MMP-12 knockout decreased both elastin breaks (Luttun et al., 2004) and buried fibrous layers (Johnson et al., 2005b). It also decreased apoptosis of FCMs (in part by stabilising cadherins) and reduced consequent calcification (Johnson et al., 2011a). On the contrary, active MMP-12 over expression in rabbits increased plaque size and inflammation (Liang et al., 2006). Both mouse and rabbit data therefore suggest that MMP-12 impairs plaque stability. Knocking out the collagenases MMP-13 and MMP-14 had little effect on macrophage or VSMC content but increased collagen in plaques, implying greater plaque stability (Deguchi et al., 2005; Schneider et al., 2008). Taken together, these findings imply that some MMPs (particularly normal levels of MMP-2, MMP-3 and MMP-9) enhance plaque stability by promoting intima formation. Others, including MMP-7, MMP-8, MMP-12, MMP-13, MMP-14 and high levels of activated MMP-9, increase matrix destruction, inflammation and/or apoptosis, which could lead to plaque rupture. Consistent with this, systemic adenovirus-mediated gene transfer of TIMP-1 or TIMP-2 improved plaque stability in two studies (Johnson et al., 2006a; Rouis et al., 1999). Moreover, prolonged over expression of TIMP-2, but not TIMP-1, prevented progression of established lesions (Johnson et al., 2006a), in part by decreasing macrophage invasion and apoptosis. This suggests that at least one MT-MMP promotes plaque instability because TIMP-2 inhibits several MT-MMPs whereas TIMP-1 does not. The studies with TIMPs provide strong support for the concept of MMP inhibition as a strategy to improve plaque stability. A clinical trial using doxycycline showed an encouraging reduction in MMP-1 levels in carotid endarterectomy samples but was too small (100 patients in total) to show clinical benefit (Axisa et al., 2002). Similarly, a trial in 50 patients with coronary artery disease demonstrated reduction in markers of systemic inflammation including MMP-9 plasma levels but clinical event rates were low in both doxyxcline and placebo treated patients (Brown et al., 2004). However, more frustratingly, studies using low molecular weight MMPi showed no effect on atherosclerosis in LDL receptor null (Prescott et al., 1999) or ApoE null (Johnson et al., 2006b; Manning et al., 2003) mice. Perhaps in these studies MMPi reached insufficient concentrations locally, although this seems unlikely given the careful experimental designs. Perhaps MMPs act redundantly with other protease classes, although why then do the single knockouts provoke effects? Perhaps the broader spectrum compared to TIMP-1 and TIMP-2 of MMPis, which also target ADAMs, abrogates their beneficial action (Peterson, 2006). Finally, and probably most likely, the reversal by MMPis of the beneficial effects of some MMPs and the adverse effect of other MMPs (see Table 1) sums to no effect over all. Two recent studies employed highly selective MMP inhibitors in mouse models. In the first a MMP-12 inhibitor (RXP470.1) with at

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least 100 fold higher potency for any other MMPs was used to treat established plaques in ApoE null mice. RXP470.1 arrested plaque enlargement, improved the ratio of VSMC to macrophages and decreased lipid core formation, macrophage apoptosis, calcification and medial elastin breaks (Johnson et al., 2011a). RXP470.1 also reduced the number of buried fibrous layers in the plaques. All of these effects were virtually identical to those obtained in MMP-12 ApoE double knockout mice (Johnson et al., 2005b). The second study used a highly selective inhibitor of MMP-13 (Quillard et al., 2011). Novel imaging methods were used to demonstrate effective inhibition of collagenolysis. Moreover the MMP-13i preserved collagen levels in the plaques to a very similar degree as seen in MMP-13 null mice (Deguchi et al., 2005) and mice transgenic for a collagenase-resistant mutant of mouse collagen-I (Fukumoto et al., 2004). These two recent studies give renewed impetus to the application of selective MMPi in atherosclerosis, although important limitations need to be mentioned. Both MMP-12 and MMP-13 are widely distributed and abundant in mouse plaques. By contrast MMP-12 is confined to deeply situated FCMs around the lipid core in human plaques (Halpert et al., 1996) and MMP-13 is less important than MMP-1 as a collagenase in man, in contrast to mice (Quillard et al., 2011). Hence the value of using selective MMPis emerges strongly from these studies but the specific choice of MMP target inhuman atherosclerosis needs further definition. Angiogenesis in the adventitia underlying plaques and within the plaque itself is associated with plaque progression and the development of vulnerability (Eriksson, 2011). The participation of MMPs in angiogenesis might therefore represent another pathogenetic mechanism and target for therapy. For example, the angiogenic peptide fibroblast growth factor-1 (FGF-1) up-regulates MMP-1 and promotes endothelial migration (Partridge et al., 2000). FGF-2 up-regulates the expression of MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11 and MMP-13 (Holnthoner et al., 2006), whereas vascular endothelial growth factor (VEGF) increases MMP-2 expression (Burbridge et al., 2002). MMP-2 and -14 are also up-regulated in rat microvascular endothelial cells in 3D collagen matrices (Haas et al., 1999; Han et al., 2003). Both MMP-14 and MMP-16 play an important role in angiogenesis (Plaisier et al., 2004; Yana et al., 2007), as reviewed (van Hinsbergh and Koolwijk, 2008), and migration of EC (Itoh, 2006), through peri-cellular proteolysis and the ability of MMP-14 to activate MMP-2. Thrombin also has proangiogenic effects by up-regulating MMP-1 and MMP-3 (Duhamel-Clérin et al., 1997) and enhancing MMP-2 activation via MMP-14 (Lafleur et al., 2001). Hepatocyte growth factor is another proangiogenic growth factor that increases MMP-14 expression and MMP-2 activation (Wang and Keiser, 2000). Perhaps most interestingly, MMP-2 and MMP-3 are found at high levels in rat in the aortic ring angiogenesis assay in fibrin culture and MMP-11 and MMP-14 in collagen; the MMPi, marimastat, inhibits angiogenesis in both collagen and fibrin matrices (Burbridge et al., 2002). Based on these findings, the effects of selective MMPis on angiogenesis in vitro and in plaques in vivo deserve further investigation. 5. Endothelial erosions Fibrous cap rupture causes 75% of MIs (see above), whereas most of the remaining MIs result from loss of a large sheet of endothelial cells in a process known as ‘erosion’ (Virmani et al., 2006). Erosions tend to occur in highly stenotic, fibrotic plaques and there is no clear association with inflammatory cells. Erosions are associated with inward and plaque ruptures outward arterial remodelling. Plaque rupture and erosion also have different risk factors; men for example are more likely to suffer ruptures and women erosions (Virmani et al., 2000). Smoking, a known cause of endothelial dysfunction, is also a strong risk factor for erosion (Arbustini et al., 1999; Burke et al., 1997, 1998), which suggests that erosion may be primarily an endothelial pathology. An attractive hypothesis is that

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over production of MMPs from inflamed or otherwise dysfunctional EC weakens their interaction with their underlying basement membrane thereby causing erosion (see Fig. 1B). MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-13, MMP-14 (MT-1 MMP), MMP-15 (MT-2 MMP) and MMP-16 (MT-3 MMP) can all be produced by endothelial cells (EC) (Burbridge et al., 2002; Castier et al., 2005; Dollery et al., 2003; Duhamel-Clérin et al., 1997; Hattori et al., 2003; Montero et al., 2006; Nagashima et al., 1997; Peracchia et al., 1997; Plaisier et al., 2004; Puyraimond et al., 2001; Wesselman et al., 2004). In addition, EC express co-activators of MMPs, including, urokinase plasminogen activator receptor (UPAR), tissue plasminogen activator (TPA), CD44, RECK, and neutrophil gelatinase-associated lipocalin (N-GAL) as well as TIMPs 1–4 (Aruffo et al., 1990; Hemdahl et al., 2006; Mandriota et al., 1995; Musso et al., 1997; Oh et al., 2004; Polette et al., 1993; Qi et al., 2003; Schleef et al., 1988). Pro-inflammatory factors can regulate MMP activity in EC. For example, TNFα upregulates MMP-1 and MMP-12 human microvascular EC (HMEC-1) (Viemann et al., 2006) and MMP-2 and -14 in human umbilical vein EC (HUVEC) under cyclic strain (Wang et al., 2003). TNFα, interleukin-1 alpha (IL-1α), IL-1β or oxidised LDL (ox-LDL) directly increase MMP-14 mRNA levels, with additive effects of TNFα and ox-LDL (Rajavashisth et al., 1999). Ox-LDL also up-regulates MMP-1 in HUVEC and human coronary artery EC and down-regulates TIMP1 (Huang et al., 2001). C reactive protein (CRP) co-ordinately increases pro-MMP-1 and its potential activator MMP-10 in EC (Montero et al., 2006). Ligation of CD40 on EC induces de novo expression of MMP-1, -3 and -9 and increases the activation of MMP-2 (Mach et al., 1999). IL-18 up-regulates MMP-1 and MMP-13 expression and also increased IL-8 production (Gerdes et al., 2002), which itself increases MMP-2 and MMP-9 (Li et al., 2003). While there is currently no animal model for erosion, breakdown of the blood brain barrier following acute brain injury supports an association between overproduction of MMPs (particularly MMP-2 and MMP-9) and loss of endothelial integrity in an in vivo setting. Moreover, a non-selective MMPi (Sood et al., 2008) or a pyrimidine2,4,6-trione MMPi selective for MMP-2, MMP-9 and MMP-14 inhibits blood brain barrier breakdown in rat models of stroke (Nagel et al., 2010). Interestingly, however, these early benefits of MMPis are nullified later on, possibly because these MMPs have a role in tissue repair (Nagel et al., 2010; Sood et al., 2008). Low average shear stress and disturbed flow are also associated with endothelial dysfunction and high risk for developing atherosclerosis, whereas physiological average, laminar shear stress (around 15 dynes/cm 2) is protective (Dai et al., 2004). Oscillatory shear up-regulates MMP-10 and -14 compared to laminar shear stress in vitro (Whalen et al., 2003; White et al., Unpublished data). Conversely, normal laminar shear stress increases MMP-1 and MMP-8 and decreases MMP-7 and MMP-14 expression (Brooks et al., 2002), the latter by phosphorylation of transcription factor Sp1 (Yun et al., 2002). The increase in MMP-1 was confirmed in a second study (Chen et al., 2001). Furthermore, over-expressing the shear induced transcription factor KLF-2 in ECs up-regulated ADAM15 and TIMP-1 (Dekker et al., 2006). How these complex changes in MMP expression impact on endothelial adhesion is not yet clear. Since erosions occur in stenotic plaques, they are likely to happen at above normal laminar shear rates. Such high shear forces are associated with adaptive, outward vessel remodelling that tends to normalise shear, for example in arteriovenous fistulas. In mice MMP-9 was upregulated in EC after carotid artery ligation (Godin et al., 2000). Moreover in the carotid–jugular fistula model, increased nitric oxide and reactive oxygen species combined to form peroxynitrite and induce the expression of MMP-9 (Castier et al., 2005; Dumont et al., 2007). Endothelial expression of MMP-9 was also up-regulated during adaptive remodelling of porcine (Southgate et al., 1999) and rabbit (Berceli et al., 2006) vein grafts.

EC can form podosomes or podosome type adhesions (PTAs), which are a type of actin and cortactin rich cellular microdomain. PTAs localise MMP-2, -9 and -14 on the surface and focus MMP degradation of the underlying matrix (Linder, 2007). This may be important in angiogenesis (Wang et al., 2009), allowing focussed degradation of the underlying basement membrane. PTAs might also be especially destructive in the context of erosions, although there is currently no direct evidence. In summary, MMP involvement in endothelial erosion is consistent with MMP and TIMP expression patterns in ECs in vitro and in animal models of related pathological states. More directly relevant in vitro and in vivo models are now needed in which to carry out the necessary MMPi, gene transfer and knockout studies. 6. Abdominal aortic aneurysms (AAAs) Aneurysms occur at a variety of locations in the body but AAAs are the most common with a prevalence of 5–8% in men aged over 65 (Golledge and Norman, 2011; Nordon et al., 2011). Small aneurysms are clinically silent but their growth beyond 55 mm or the presence of symptoms presages increased risk of rupture with high subsequent mortality (Golledge and Norman, 2011). Surgical repair or endovascular treatment can stabilise large aneurysms, although subsequent mortality and morbidity remain high (Golledge and Norman, 2011; Nordon et al., 2011). Hence there is an urgent need to identify medical therapies for prevention or as an adjunct to intervention. Initially thought to be a consequence of atherosclerosis, profound differences in some risk factors (Nordon et al., 2011), indifferent responses to therapies effective against atherosclerosis (Golledge and Norman, 2011) and genetic evidence (Lindsay and Dietz, 2011), among other factors, argue strongly for a different aetiology. It seems that AAA may be a local manifestation of a systemic pathology of the vascular extracellular matrix (Nordon et al., 2011). Furthermore pathological observations suggest that the earliest events may be loss of elastin mediated by VSMCs, perhaps as a result of inflammatory activation (see Fig. 1C) and only later by influx of leukocytes in response to the production of ECM fragments with chemotactic activity (Thompson and Cockerill, 2006). This suggests a multi-stage, initiation and destabilisation, paradigm for aneurysm growth and rupture (see Fig. 1C). Initial loss of elastin in the medial layer causes compensatory fibrosis leading to normal or increased collagen deposition (Fig. 1C). Later destruction of all major matrix components as a consequence of inflammation causes further distension (see Fig. 1C) and eventually rupture (not shown). Consistent with this, imaging studies and pathological examinations of advanced AAAs demonstrate an association between leukocyte infiltration and likelihood of rupture (Hong et al., 2010; Reeps et al., 2008). A multi-stage paradigm may have important implications for the pathogenetic role of MMPs and the identification of different treatment targets for aneurysm enlargement and rupture. Availability of early-stage aneurysm tissue is limited because surgical resection confers no benefit for the treatment of small aneurysms (Participants, 1998). However, there appears to be a paucity of inflammatory cells in early aneurysm tissue, where elastin destruction in the medial layer is associated with production from VSMCs of MMP-2 (Crowther et al., 2000; Goodall et al., 2001), which is a constitutively expressed protein in VSMC (Newby, 2006). Other constitutive proteins, TIMP-2 and MT1-MMP, are also present (Goodall et al., 2001), which provides a plausible mechanism for activation of pro-MMP-2 (Davis et al., 1998; Nollendorfs et al., 2001). TIMP-1 is up-regulated, perhaps as a compensatory mechanism (Yamashita et al., 2001). Interestingly, MMP-9 which is only found in VSMC after inflammatory activation (Newby, 2006), is not prominent in early disease samples (Crowther et al., 2000; Goodall et al., 2001). However, other studies found that the interstitial collagenase MMP-13 was up-regulated in VSMCs of aneurysms (Mao et al., 1999; Tromp et al., 2004), which may imply that VSMCs are

already activated by inflammatory cytokines in these early lesions. In advanced surgically removed aneurysms with prominent inflammatory infiltrates MMP-8, MMP-9, MMP-12, and MMP-19 and TIMP-3 become detectable (Carrell et al., 2002; Curci et al., 1998a; Jackson et al., 2011; Petersen et al., 2000; Sakalihasan et al., 1996; Thompson et al., 1995; Wilson et al., 2005, 2006). These MMPs and TIMP-3 are abundant constitutively in human monocytes and macrophages (Reel et al., 2011) and could therefore simply reflect recruitment of these cells to the lesions. However, there was also evidence for increased levels of MMP-3 (Carrell et al., 2002), which is only detected at high levels after inflammatory activation of monocytes and macrophages (Reel et al., 2011). MMP-9 complexed to N-GAL (Folkesson et al., 2007) and the regulator of MMPs activity, EMMPRIN, are also present (Chen et al., 2009; Lizarbe et al., 2009). Protease of other classes including tissue plasminogen activator (Saito et al., 2002) and several cathepsins with collagenloytic activity (Abdul-Hussien et al., 2007) also occur together with the MMPs. The appearance of MMP-9, MMP-12 and MMP-19 has been localized to inflammatory cells in several studies (Curci et al., 1998a; Jackson et al., 2011; Sakalihasan et al., 1996; Thompson et al., 1995), although others found MMP-9 located in so-called mesenchymal adventitial cells (Wilson et al., 2005, 2006). MMP-9 levels were related to aneurysm rupture in one study (Petersen et al., 2000) but not in another (Papalambros et al., 2003). The tentative conclusion is that several MMPs are already present and activated in the VSMCs of early aneurysms but that others are recruited to advanced aneurysms through inflammation. Adventitial angiogenesis has been suggested as potential route for inflammatory cells and a source of additional MMP activity (Tedesco et al., 2009). A factor that may influence both early and late stages of AAA pathology is aberrant modulation of transforming growth factor-β (TFG-β) and related pathways, since TFG-β normally has a major role in up-regulating synthesis of ECM components (Lindsay and Dietz, 2011), reducing the production of vascular MMPs and increasing TIMPs (Newby, 2005) and suppressing inflammation (Tedgui and Mallat, 2006). A common consequence of defective TGF-β signalling might be activation of c-jun N terminal kinase, which promotes aneurysms (Yoshimura et al., 2005) and has a major role in induction of MMP genes in VSMC and macrophages (Clark et al., 2008; Reel et al., 2011). A variety of models have been developed (see Tables 2, 3) to mimic the processes of aneurysm formation, using organ cultures, rats and increasingly mice in order to investigate the effects of MMP and TIMP gene deletions (Table 2). Models include treating the arteries locally with CaCl2 or elastase or animals systemically with a combination of angiotensin II and antibodies against TGF-β. Table 2 MMP knockout studies showing decreased aneurysm formation. Model

Knockout (not effective in parenthesis)

Reference

Mouse elastase

MMP-9, MMP-9 BM (MMP-12)

Mouse CaCl2 Mouse CaCl2

MMP2, MMP-9 (MMP-2 bone marrow), MMP-9 bone marrow MMP-9 despite up-regulation of MMP-2

Mouse CaCl2

TIMP-2 by reducing activation of MMP-2

Mouse elastase

MMP-13

Mouse CaCl2

MMP-14 bone marrow

Mouse CaCl2

MMP-12

Pyo et al. (2000) Longo et al. (2002) Ikonomidis et al. (2005) Xiong et al. (2006) Lizarbe et al. (2009) Xiong et al. (2009) Longo et al. (2005) Wang et al. (2010)

Mouse angiotensin II MMP-12 and anti-TGF-β

Citations are organised in chronological order. Knockouts decrease aneurysm formation except for those indicated in parentheses which had no measureable effect.

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Table 3 Studies on aortic aneurysms with MMP inhibitors. Model

MMP inhibitor (not effective in parenthesis)

Rat elastase

Doxycycline reduced size, MMP-9 activity, Petrinec et al. (inflammation) (1996) Doxycycline and other tetracyclines Curci et al. (1998b) Doxycycline, elastin preservation Boyle et al. (1998) BB94, smaller, less inflamed Bigatel et al. (1999) RS 132908, smaller, elastin (collagen) Moore et al. preservation (inflammation) (1999) Marimastat, elastin preservation Treharne et al. (1999)

Rat elastase Pig organ culture CaCl2 Rat elastase Rat elastase Pig organ culture elastase Human Mouse elastase Human Mouse CaCl2 ApoE null Angiotensin II Human organ culture Mouse elastase Mouse CaCl2 Mouse elastase Mouse fibulin1 mutation Mouse fibulin1 mutation ApoE null Angiotensin II Human

Doxycycline reduced MMP-2 and MMP-9 expression Doxycycline, elastin preservation (inflammation) Doxycycline decreased MMP-9 mRNA and protein and activated MMP-2 Escalating doses of doxycycline Doxycycline decreased aneurysms (atherosclerosis) Doxycycline decreased pro- and active forms of MMP-2 and MMP-9 Locally delivered doxycycline JNK inhibitor SP600125 reduced size, MMP-9 expression and preserved elastin Locally delivered doxycycline Doxycycline, preserves elastin and decreases MMP-2 and MMP-9 activity Doxycycline, combined antibodies to MMP-2 and MMP-9

Doxycycline decreased size and MMP-2 and MMP-9 activity Doxycycline decreased neutrophils, T-cells and interleukins-6, -8 and − 13 ApoE null Doxycycline or a histone deacetylase Angiotensin II inhibitor decreased size and MMP-2 and MMP-9 activity Mouse CaCl2 Doxycycline decreased size and MMP activity ApoE null Doxycycline or an angiogenesis inhibitor Angiotensin II Human Doxycycline decreased MMP-3 and MMP-25 mRNA, MMP-8 and MMP-9 protein, increased TIMP-1 and cystatin C protein Doxycycline with losartan Mouse decreased size and fibulin1 MMP activity mutation

Reference

Thompson and Baxter (1999) Pyo et al. (2000) Curci et al. (2000) Prall et al. (2002) Manning et al. (2003) Liu et al. (2003) Sho et al. (2004) Yoshimura et al. (2005) Bartoli et al. (2006) Xiong et al. (2008) Chung et al. (2008) Turner et al. (2008) Lindeman et al. (2009) Vinh et al. (2008) Sheth et al. (2010) Tedesco et al. (2009) Abdul-Hussien et al. (2009)

Yang et al. (2010)

Citations are organised in chronological order. The MMPis specified produced effects consistent with reduction in aneurysm formation or underlying biological processes as indicated. Negative effects are reported in parentheses.

Alternatively, hypercholesterolaemic ApoE null mice infused with angiotensin II have been used. Finally, genetic models, particular with decreased fibulin1 production and function have been developed (see Tables 2, 3). Based on these models it was discovered that knockout of MMP-2 and MMP-9 reduced aneurysm formation significantly (Ikonomidis et al., 2005; Longo et al., 2002; Pyo et al., 2000). Knockout of TIMP-2 also decreased aneurysms in the CaCl2 model by reducing the activation of MMP-2 (Xiong et al., 2006). Interestingly, the important source of MMP-2 appeared to be the VSMCs, whereas MMP-9 came from macrophages (Longo et al., 2002; Pyo et al., 2000). Activity of the elastase MMP-12 was not required in the pancreatic elastase model (Pyo et al., 2000) but was in the CaCl2 (Longo et al., 2005) and the angiotensin-II plus anti-

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TGF-β models (Wang et al., 2010). MMP-13, which is an abundant collagenase in mice but not humans, reduced aneurysms in the elastase model (Lizarbe et al., 2009). Bone marrow derived MMP-14 reduced aneurysms in vessels treated with CaCl2 and this appeared to be a direct effect not mediated through decreased activation of MMP-2 (Xiong et al., 2009). Urokinase-type plasminogen activator (uPA), a putative activator of several pro-MMPs, has also been implicated in aneurysms from knockout studies in ApoE null mice (Deng et al., 2003), although recent studies in LDL receptor null mice suggested a protective role. So far at least 23 studies have investigated the effects of MMPis or pleiotropic agents with MMPi activity in recovered human tissue, organ culture or animal models of AAA (see Table 3). From the first (Petrinec et al., 1996), 19 of these studies used doxycycline, which was effective when delivered systemically or locally (Bartoli et al., 2006; Sho et al., 2004) (Table 3). Several studies confirmed that doxycycline reduced MMP expression as well as activity (Abdul-Hussien et al., 2009; Curci et al., 2000; Liu et al., 2003; Petrinec et al., 1996; Sheth et al., 2010; Thompson and Baxter, 1999; Vinh et al., 2008; Xiong et al., 2008; Yang et al., 2010), which is consistent with its mechanism of action on isolated VSMCs (Liu et al., 2003) and macrophages (Curci et al., 2000). In one study a combination of antibodies to MMP-2 and MMP-9 was as effective as doxycycline (Chung et al., 2008). The active-site directed MMPis, BB-94, RS 132908 and merimastat were also effective in several models (Bigatel et al., 1999; Moore et al., 1999; Treharne et al., 1999) (Table 3). There is general agreement that MMPis reduced elastin degradation, but whereas one clinical (Lindeman et al., 2009) and one animal study reported reduced inflammation (Bigatel et al., 1999), three others reported no reduction (Moore et al., 1999; Petrinec et al., 1996; Pyo et al., 2000). The requirement of MMPs for recruitment of inflammatory cells is therefore uncertain. Of possible clinical relevance, in another study, doxycycline was shown to synergise with angiotensin converting enzyme inhibitor losartan (Yang et al., 2010). Pleiotropic agents that might reduce aneurysms in part by decreasing MMP activity are inhibitors of histone deacetylase (Vinh et al., 2008) and c-jun N-terminal kinase (Yoshimura et al., 2005). Indeed activation of c-jun N-terminal kinase is a key mechanism in MMP upregulation in VSMCs (Yoshimura et al., 2005) and monocyte macrophages (Reel et al., 2011). So far six controlled trials and two registry studies have addressed the clinical impact of doxycycline on AAAs (Abdul-Hussien et al., 2009; Baxter et al., 2002; Curci et al., 2000; Ding et al., 2005; Hackmann et al., 2008; Liu et al., 2003; Mosorin et al., 2001; Thompson and Baxter, 1999). Where looked for (Baxter et al., 2002; Mosorin et al., 2001), no clear benefit was seen on progression of aneurysm size. However, this conclusion is not definitive because the studies were underpowered for this endpoint and there were other compromises in experimental design (Dodd and Spence, 2011). Two large, pivotal trials are in progress and the outcome is eagerly awaited (Golledge and Norman, 2011). 7. Conclusions MMPs as an enzyme family have well-established roles in several vascular pathologies including intima formation, atherosclerosis and aneurysms. Other pathologies including endothelial erosion require more preclinical studies to define the role of MMPs. The functions of individual MMPs have been established from associative studies in human pathological tissues, biochemical and cell biological studies of cells and tissues in culture, and genetic manipulation mainly in mice. As part of this work gene transfer of TIMPs with viruses or by transgenesis has proven effective in reducing MMP activity and reversing several pathologies. However, the use of broad spectrum synthetic MMPis has not always replicated the effects of TIMPs in preclinical models, possibly owing to off-target effects and also

because MMPs clearly have reparative as well as pathogenetic roles. The emphasis has therefore shifted to the development of MMPi of restricted specificity, with inhibitors of MMP-12 and MMP-13 recently in the vanguard because selective MMPi accurately replicated the phenotypes of the related knockout mice (Johnson et al., 2011a; Quillard et al., 2011). Hence, with caveats about the comparability of MMP expression and regulation between mice and man, these studies provide new impetus for early clinical trials, especially in the context of acute myocardial infarction and aneurismal dilatation. Acknowledgements Thanks are owing to Dr Jason L. Johnson for the photomicrographs of mouse plaques in the graphic abstract, to Dr Buket Reel for references to bisphosphonates and to Dr Stephen J White for some references to MMPs in endothelial cells. The authors' work is supported by The British Heart Foundation and by the NIHR Bristol Cardiovascular Biomedical Research Unit. References Abdul-Hussien, H., Soekhoe, R.G., Weber, E., von der Thusen, J.H., Kleemann, R., Mulder, A., van Bockel, J.H., Hanemaaijer, R., Lindeman, J.H., 2007. Collagen degradation in the abdominal aneurysm: a conspiracy of matrix metalloproteinase and cysteine collagenases. Am. J. Pathol. 170, 809–817. Abdul-Hussien, H., Hanemaaijer, R., Verheijen, J.H., van Bockel, J.H., Geelkerken, R.H., Lindeman, J.H., 2009. Doxycycline therapy for abdominal aneurysm: improved proteolytic balance through reduced neutrophil content. J. Vasc. Surg. 49, 741–749. Agrawal, A., Romero-Perez, D., Jacobsen, J.A., Villarreal, F.J., Cohen, S.M., 2008. Zincbinding groups modulate selective inhibition of MMPs. ChemMedChem 3, 812–820. Aguilera, C.M., George, S.J., Johnson, J.L., Newby, A.C., 2003. Relationship between type IV collagen degradation, metalloproteinase activity and smooth muscle cell migration and proliferation in cultured human saphenous vein. Cardiovasc. Res. 58, 679–688. Arbustini, E., Dal Bello, B., Morbini, P., Burke, A.P., Bocciarelli, M., Specchia, G., Virmani, R., 1999. Plaque erosion is a major substrate for coronary thrombosis in acute myocardial infarction. Heart 82, 269–272. Aruffo, A., Stamenkovic, I., Melnick, M., Underhill, C.B., Seed, B., 1990. Cd44 is the principal cell-surface receptor for hyaluronate. Cell 61, 1303–1313. Axisa, B., Loftus, I.M., Naylor, A.R., Goodall, S., Jones, L., Bell, P.R., Thompson, M.M., 2002. Prospective, randomized, double-blind trial investigating the effect of doxycycline on matrix metalloproteinase expression within atherosclerotic carotid plaques. Stroke 33, 2858–2864. Baker, A.H., Zaltsman, A.B., George, S.J., Newby, A.C., 1998. Divergent effects of tissue inhibitors of metalloproteinase-1, -2 or -3 on rat vascular smooth muscle cell invasion, proliferation and death in vitro: TIMP-3 promotes apoptosis. J. Clin. Invest. 101, 1478–1487. Bar-Or, A., Nuttall, R.K., Duddy, M., Alter, A., Kim, H.J., Ifergan, I., Pennington, C.J., Bourgoin, P., Edwards, D.R., Yong, V.W., 2003. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis. Brain 126, 2738–2749. Bartoli, M.A., Parodi, F.E., Chu, J., Pagano, M.B., Mao, D., Baxter, B.T., Buckley, C., Ennis, T.L., Thompson, R.W., 2006. Localized administration of doxycycline suppresses aortic dilatation in an experimental mouse model of abdominal aortic aneurysm. Ann. Vasc. Surg. 20, 228–236. Baxter, B.T., Pearce, W.H., Waltke, E.A., Littooy, F.N., Hallett Jr., J.W., Kent, K.C., Upchurch Jr., G.R., Chaikof, E.L., Mills, J.L., Fleckten, B., Longo, G.M., Lee, J.K., Thompson, R.W., 2002. Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study. J. Vasc. Surg. 36, 1–12. Bendeck, M.P., Irvin, C., Reidy, M.A., 1996. Inhibition of matrix metalloproteinase activity inhibits smooth muscle cell migration but not neointimal thickening after arterial injury. Circ. Res. 78, 38–43. Bendeck, M.P., Conte, M., Zhang, M., Nili, N., Strauss, B.H., Farwell, S.M., 2002. Doxycycline modulates smooth muscle cell growth, migration, and matrix remodeling after arterial injury. Am. J. Pathol. 160, 1089–1095. Berceli, S.A., Jiang, Z.H., Klingman, N.V., Schultz, G.S., Ozaki, C.K., 2006. Early differential MMP-2 and-9 dynamics during flow-induced arterial and vein graft adaptations. J. Surg. Res. 134, 327–334. Bigatel, D.A., Elmore, J.R., Carey, D.J., Cizmeci-Smith, G., Franklin, D.P., Youkey, J.R., 1999. The matrix metalloproteinase inhibitor BB-94 limits expansion of experimental abdominal aortic aneurysms. J. Vasc. Surg. 29, 130–138 discussion 138–139. Bond, M., Chase, A.J., Baker, A.H., Newby, A.C., 2001. Inhibition of transcription factor NF-κB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc. Res. 50, 556–565. Boyle, J.R., McDermott, E., Crowther, M., Wills, A.D., Bell, P.R., Thompson, M.M., 1998. Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease. J. Vasc. Surg. 27, 354–361.

Brooks, A.R., Lelkes, P.I., Rubanyi, G.M., 2002. Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiol. Genomics 9, 27–41. Brown, D.L., Desai, K.K., Vakili, B.A., Nouneh, C., Lee, H.-M., Golub, L.M., 2004. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial. Arterioscler. Thromb. Vasc. Biol. 24, 733–738. Burbridge, M.F., Cogé, F., Galizzi, J.P., Boutin, J.A., West, D.C., Tucker, G.C., 2002. The role of the matrix metalloproteinases during in vitro vessel formation. Angiogenesis 5, 215–226. Burke, A.P., Farb, A., Malcom, G.T., Liang, Y.H., Smialek, J., Virmani, R., 1997. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N. Engl. J. Med. 336, 1276–1282. Burke, A.P., Farb, A., Malcom, G.T., Liang, Y., Smialek, J., Virmani, R., 1998. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation 97, 2110–2116. Carrell, T.W., Burnand, K.G., Wells, G.M., Clements, J.M., Smith, A., 2002. Stromelysin-1 (matrix metalloproteinase-3) and tissue inhibitor of metalloproteinase-3 are overexpressed in the wall of abdominal aortic aneurysms. Circulation 105, 477–482. Castier, Y., Brandes, R.P., Leseche, G., Tedgui, A., Lehoux, S., 2005. P47phox-dependent NADPH oxidase regulates flow-induced vascular remodeling. Circ. Res. 97, 533–540. Chase, A., Bond, M., Crook, M.F., Newby, A.C., 2002. Role of nuclear factor-κB activation in metalloproteinase-1, -3 and -9 secretion by human macrophages in vitro and rabbit foam cells produced in vivo. Arterioscler. Thromb. Vasc. Biol. 22, 765–771. Chen, B.P.C., Li, Y.-S., Zhao, Y., Chen, K.-D., Li, S., Lao, J., Yuan, S., Shyy, J.Y.J., Chien, S.H.U., 2001. DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress. Physiol. Genomics 7, 55–63. Chen, X.F., Wang, J.A., Hou, J., Gui, C., Tang, L.J., Chen, X.Q., Xie, X.J., Jiang, J.J., Cai, J.F., Chen, H.S., Lu, H.S., Chen, H., 2009. Extracellular matrix metalloproteinase inducer (EMMPRIN) is present in smooth muscle cells of human aneurysmal aorta and is induced by angiotensin II in vitro. Clin. Sci. (Lond) 116, 819–826. Cheng, L., Mantile, G., Pauly, R., Nater, C., Felici, A., Monticone, R., Bilato, C., Gluzband, Y.A., Crow, M.T., Stetler-Stevenson, W., Capogrossi, M.C., 1998. Adenovirus-mediated gene transfer of the human tissue inhibitor of metalloproteinase-2 blocks vascular smooth muscle cell invasiveness in vitro and modulates neointimal development in vivo. Circulation 98, 2195–2201. Cherr, G.S., Motew, S.J., Travis, J.A., Fingerle, J., Fisher, L., Brandl, M., Williams, J.K., Geary, R.L., 2002. Metalloproteinase inhibition and the response to angioplasty and stenting in atherosclerotic primates. Arterioscler. Thromb. Vasc. Biol. 22, 161–166. Cho, A., Reidy, M.A., 2002. Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury. Circ. Res. 91, 845–851. Chung, A.W., Yang, H.H., Radomski, M.W., van Breemen, C., 2008. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ. Res. 102, e73–e85. Clark, J.C., Thomas, D.M., Choong, P.F., Dass, C.R., 2007. RECK—a newly discovered inhibitor of metastasis with prognostic significance in multiple forms of cancer. Cancer Metastasis Rev. 26, 675–683. Clark, I.M., Swingler, T.E., Sampieri, C.L., Edwards, D.R., 2008. The regulation of matrix metalloproteinases and their inhibitors. Int. J. Biochem. Cell Biol. 40, 1362–1378. Clutterbuck, A.L., Asplin, K.E., Harris, P., Allaway, D., Mobasheri, A., 2009. Targeting matrix metalloproteinases in inflammatory conditions. Curr. drug targets 10, 1245–1254. Crowther, M., Goodall, S., Jones, J.L., Bell, P.R., Thompson, M.M., 2000. Localization of matrix metalloproteinase 2 within the aneurysmal and normal aortic wall. Br. J. Surg. 87, 1391–1400. Curci, J.A., Liao, S., Huffman, M.D., Shapiro, S.D., Thompson, R.W., 1998a. Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms. J. Clin. Invest. 102, 1900–1910. Curci, J.A., Petrinec, D., Liao, S., Golub, L.M., Thompson, R.W., 1998b. Pharmacologic suppression of experimental abdominal aortic aneurysms: a comparison of doxycycline and four chemically modified tetracyclines. J. Vasc. Surg. 28, 1082–1093. Curci, J.A., Mao, D., Bohner, D.G., Allen, B.T., Rubin, B.G., Reilly, J.M., Sicard, G.A., Thompson, R.W., 2000. Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms. J. Vasc. Surg. 31, 325–342. Dai, G.H., Kaazempur-Mofrad, M.R., Natarajan, S., Zhang, Y.Z., Vaughn, S., Blackman, B.R., Kamm, R.D., Garcia-Cardena, G., Gimbrone, M.A., 2004. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosissusceptible and -resistant regions of human vasculature. Proc. Natl. Acad. Sci. U. S. A. 101, 14871–14876. Davis, V., Persidskaia, R., Baca-Regen, L., Itoh, Y., Nagase, H., Persidsky, Y., Ghorpade, A., Baxter, B.T., 1998. Matrix metalloproteinase-2 production and its binding to the matrix are increased in abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 18, 1625–1633. de Nooijer, R., Verkleij, C.J.N., von der Thusen, J.H., Jukema, J.W., van der Wall, E.E., van Berkel, T.J.C., Baker, A.H., Biessen, E.A.L., 2006. Lesional overexpression of matrix metalloproteinase-9 promotes intraplaque hemorrhage in advanced lesions but not at earlier stages of atherogenesis. Arterioscler. Thromb. Vasc. Biol. 26, 340–346. Deguchi, J.-O., Aikawa, E., Libby, P., Vachon, J.R., Inada, M., Krane, S.M., Whittaker, P., Aikawa, M., 2005. Matrix metalloproteinase-13/collagenase-3 deletion promotes collagen accumulation and organization in mouse atherosclerotic plaques. Circulation 112, 2708–2715. Dekker, R.J., Boon, R.A., Rondaij, M.G., Kragt, A., Volger, O.L., Elderkamp, Y.W., Meijers, J.C.M., Voorberg, J., Pannekoek, H., Horrevoets, A.J.G., 2006. KLF2 provokes a gene

241

expression pattern that establishes functional quiescent differentiation of the endothelium. Blood 107, 4354–4363. Deng, G.G., Martin-McNulty, B., Sukovich, D.A., Freay, A., Halks-Miller, M., Thinnes, T., Loskutoff, D.J., Carmeliet, P., Dole, W.P., Wang, Y.X., 2003. Urokinase-type plasminogen activator plays a critical role in angiotensin II-induced abdominal aortic aneurysm. Circ. Res. 92, 510–517. Devel, L., Rogakos, V., David, A., Makaritis, A., Beau, F., Cuniasse, P., Yiotakis, A., Dive, V., 2006. Development of selective inhibitors and substrate of matrix metalloproteinase-12. J. Biol. Chem. 281, 11152–11160. Devy, L., Dransfield, D.T., 2011. New strategies for the next generation of matrixmetalloproteinase inhibitors: selectively targeting membrane-anchored MMPs with therapeutic antibodies. Biochem. Res. Int. 2011. Devy, L., Huang, L., Naa, L., Yanamandra, N., Pieters, H., Frans, N., Chang, E., Tao, Q., Vanhove, M., Lejeune, A., van Gool, R., Sexton, D.J., Kuang, G., Rank, D., Hogan, S., Pazmany, C., Ma, Y.L., Schoonbroodt, S., Nixon, A.E., Ladner, R.C., Hoet, R., Henderikx, P., Tenhoor, C., Rabbani, S.A., Valentino, M.L., Wood, C.R., Dransfield, D.T., 2009. Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 69, 1517–1526. Ding, R., McGuinness, C.L., Burnand, K.G., Sullivan, E., Smith, A., 2005. Matrix metalloproteinases in the aneurysm wall of patients treated with low-dose doxycycline. Vascular 13, 290–297. Dodd, B.R., Spence, R.A., 2011. Doxycycline Inhibition of Abdominal Aortic Aneurysm Growth - A Systematic Review of the Literature. Current vascular pharmacology 9, 471–478. Dollery, C.M., Humphries, S.E., McClelland, A., Latchman, D.S., McEwan, J.R., 1999. Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury. Circulation 99, 3199–3205. Dollery, C.M., Owen, C.A., Sukhova, G.K., Krettek, A., Shapiro, S.D., Libby, P., 2003. Neutrophil elastase in human atherosclerotic plaques. Production by macrophages. Circ. Res. 107, 2829–2836. Dorman, G., Cseh, S., Hajdu, I., Barna, L., Konya, D., Kupai, K., Kovacs, L., Ferdinandy, P., 2010. Matrix metalloproteinase inhibitors: a critical appraisal of design principles and proposed therapeutic utility. Drugs 70, 949–964. Duhamel-Clérin, E., Orvain, C., Lanza, F., Cazenave, J.-P., Klein-Soyer, C., 1997. Thrombin receptor-mediated increase of two matrix metalloproteinases, MMP-1 and MMP-3 in human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 17, 1931–1938. Dumont, O., Loufrani, L., Henrion, D., 2007. Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries. Arterioscler. Thromb. Vasc. Biol. 27, 317–324. Dwivedi, A., Slater, S.C., George, S.J., 2009. MMP-9 and -12 cause N-cadherin shedding and thereby beta-catenin signalling and vascular smooth muscle cell proliferation. Cardiovasc. Res. 81, 178–186. Engel, C.K., Pirard, B., Schimanski, S., Kirsch, R., Habermann, J., Klingler, O., Schlotte, V., Weithmann, K.U., Wendt, K.U., 2005. Structural basis for the highly selective inhibition of MMP-13. Chem. Biol. 12, 181–189. Eriksson, E.E., 2011. Intravital microscopy on atherosclerosis in apolipoprotein Edeficient mice establishes microvessels as major entry pathways for leukocytes to advanced lesions/clinical perspective. Circulation 124, 2129–2138. Filippov, S., Koenig, G.C., Chun, T.H., Hotary, K.B., Ota, I., Bugge, T.H., Roberts, J.D., Fay, W.P., Birkedal-Hansen, H., Holmbeck, K., Sabeh, F., Allen, E.D., Weiss, S.J., 2005. MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells. J. Exp. Med. 202, 663–671. Folkesson, M., Kazi, M., Zhu, C., Silveira, A., Hemdahl, A.L., Hamsten, A., Hedin, U., Swedenborg, J., Eriksson, P., 2007. Presence of NGAL/MMP-9 complexes in human abdominal aortic aneurysms. Thromb. Haemost. 98, 427–433. Forough, R., Koyama, M., Hasenstab, D., Lea, H., Clowes, M., Nikkari, S.T., Clowes, A.W., 1996. Overexpression of tissue inhibitor of matrix metalloproteinase-1 inhibits vascular smooth muscle cell functions in vitro and in vivo. Circ. Res. 79, 812–820. Franco, C., Ho, B., Mulholland, D., Hou, G., Islam, M., Donaldson, K., Bendeck, M.P., 2006. Doxycycline alters vascular smooth muscle cell adhesion, migration, and reorganization of fibrillar collagen matrices. Am. J. Pathol. 168, 1697–1709. Fukumoto, Y., Deguchi, J.-O., Libby, P., Rabkin-Aikawa, E., Sakata, Y., Chin, M.T., Hill, C.C., Lawler, P.R., Varo, N., Schoen, F.J., Krane, S.M., Aikawa, M., 2004. Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques. Circulation 110, 1953–1959. Galis, Z.S., Johnson, C., Godin, D., Magid, R., Shipley, J.M., Senior, R.M., Ivan, E., 2002. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ. Res. 91, 852–859. George, S.J., Angelini, G.D., Newby, A.C., Baker, A.H., 1998a. Adenovirus mediated gene transfer of the human TIMP-1 gene inhibits smooth muscle cell migration and neointima formation in human saphenous vein. Hum. Gene Ther. 9, 867–877. George, S.J., Baker, A.H., Angelini, G.D., Newby, A.C., 1998b. Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins. Gene Ther. 5, 1552–1560. George, S.J., Lloyd, C.T., Angelini, G.D., Newby, A.C., Baker, A.H., 2000. Gene therapy for vein graft disease: tissue inhibitor of metalloproteinase-3 inhibits metalloproteinases, promotes apoptosis and reduces neointima formation in vitro and in vivo. Circulation 101, 296–304. George, S.J., Wan, S., Hu, J., MacDonald, R., Johnson, J.L., Baker, A.H., 2011. Sustained reduction of vein graft neointima formation by ex vivo TIMP-3 gene therapy. Circulation 124, S135–S142. Gerdes, N., Sukhova, G.K., Libby, P., Reynolds, R.S., Young, J.L., Schonbeck, U., 2002. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J. Exp. Med. 195, 245–257.

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A.C. Newby / Vascular Pharmacology 56 (2012) 232–244

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242

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Godin, D., Ivan, E., Johnson, C., Magid, R., Galis, Z.S., 2000. Remodeling of carotid artery is associated with increased expression of matrix metalloproteinases in mouse blood flow cessation model. Circulation 102, 2861–2866. Golledge, J., Norman, P.E., 2011. Current status of medical management for abdominal aortic aneurysm. Atherosclerosis 217, 57–63. Goodall, S., Crowther, M., Hemingway, D.M., Bell, P.R., Thompson, M.M., 2001. Ubiquitous elevation of matrix metalloproteinase-2 expression in the vasculature of patients with abdominal aneurysms. Circulation 104, 304–309. Gough, P.J., Gomez, I.G., Wille, P.T., Raines, E.W., 2006. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J. Clin. Invest. 116, 59–69. Grams, F., Brandstetter, H., D'Alo, S., Geppert, D., Krell, H.W., Leinert, H., Livi, V., Menta, E., Oliva, A., Zimmermann, G., Gram, F., Livi, V.E., 2001. Pyrimidine-2,4,6-Triones: a new effective and selective class of matrix metalloproteinase inhibitors. Biol. Chem. 382, 1277–1285. Guenther, A., Gordon, S., Tiemann, M., Burger, R., Bakker, F., Green, J.R., Baum, W., Roelofs, A.J., Rogers, M.J., Gramatzki, M., 2010. The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation. Int. J. Cancer 126, 239–246. Haas, T.L., Stitelman, D., Davis, S.J., Apte, S.S., Madri, J.A., 1999. Egr-1 mediates extracellular matrix-driven transcription of membrane type 1 matrix metalloproteinase in endothelium. J. Biol. Chem. 274, 22679–22685. Hackmann, A.E., Rubin, B.G., Sanchez, L.A., Geraghty, P.A., Thompson, R.W., Curci, J.A., 2008. A randomized, placebo-controlled trial of doxycycline after endoluminal aneurysm repair. J. Vasc. Surg. 48, 519–526 discussion 526. Hajduk, P.J., Shuker, S.B., Nettesheim, D.G., Craig, R., Augeri, D.J., Betebenner, D., Albert, D.H., Guo, Y., Meadows, R.P., Xu, L., Michaelides, M., Davidsen, S.K., Fesik, S.W., 2002. NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability. J. Med. Chem. 45, 5628–5639. Halpert, I., Sires, U.I., Roby, J.D., PotterPerigo, S., Wight, T.N., Shapiro, S.D., Welgus, H.G., Wickline, S.A., Parks, W.C., 1996. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc. Natl. Acad. Sci. U. S. A. 93, 9748–9753. Han, X.Y., Boyd, P.J., Colgan, S., Madri, J.A., Haas, T.L., 2003. Transcriptional upregulation of endothelial cell matrix metalloproteinase-2 in response to extracellular cues involves GATA-2. J. Biol. Chem. 278, 47785–47791. Hattori, Y., Nerusu, K.C., Bhagavathula, N., Brennan, M., Hattori, N., Murphy, H.S., Su, L.D., Wang, T.S., Johnson, T.M., Varani, J., 2003. Vascular expression of matrix metalloproteinase-13 (collagenase-3) in basal cell carcinoma. Exp. Mol. Pathol. 74, 230–237. Hemdahl, A.-L., Gabrielsen, A., Zhu, C., Eriksson, P., Hedin, U., Kastrup, J., Thoren, P., Hansson, G.K., 2006. Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 26, 136–142. Herman, M.P., Sukhova, G.K., Libby, P., Gerdes, N., Tang, N., Horton, D.B., Kilbride, M., Breitbart, R.E., Chun, M., Schonbeck, U., 2001. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation 104, 1899–1904. Holnthoner, W., Kerenyi, M., Groger, M., Kratochvill, F., Petzelbauer, P., 2006. Regulation of matrilysin expression in endothelium by fibroblast growth factor-2. Biochem. Biophys. Res. Commun. 342, 725–733. Hong, H., Yang, Y., Liu, B., Cai, W., 2010. Imaging of abdominal aortic aneurysm: the present and the future. Curr. Vasc. Pharmacol. 8, 808–819. Hu, J., Van den Steen, P.E., Sang, Q.X., Opdenakker, G., 2007. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat. Rev. Drug Discov. 6, 480–498. Huang, Y., Song, L.X., Wu, S., Fan, F., Lopes-Virella, M.F., 2001. Oxidized LDL differentially regulates MMP-1 and TIMP-1 expression in vascular endothelial cells. Atherosclerosis 156, 119–125. Ikonomidis, J.S., Barbour, J.R., Amani, Z., Stroud, R.E., Herron, A.R., McClister Jr., D.M., Camens, S.E., Lindsey, M.L., Mukherjee, R., Spinale, F.G., 2005. Effects of deletion of the matrix metalloproteinase 9 gene on development of murine thoracic aortic aneurysms. Circulation 112, I242–I248. Islam, M.M., Franco, C.D., Courtman, D.W., Bendeck, M.P., 2003. A nonantibiotic chemically modified tetracycline (CMT-3) inhibits intimal thickening. Am. J. Pathol. 163, 1557–1566. Itoh, Y., 2006. MT1-MMP: a key regulator of cell migration in tissue. IUBMB Life 58, 589–596. Jackson, V., Olsson, T., Kurtovic, S., Folkersen, L., Paloschi, V., Wagsater, D., FrancoCereceda, A., Eriksson, P., 2011. Matrix metalloproteinase 14 and 19 expression is associated with thoracic aortic aneurysms. J. Thorac. Cardiovasc. Surg. Johnson, C., Galis, Z.S., 2004. Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization. Arterioscler. Thromb. Vasc. Biol. 24, 54–60. Johnson, J.L., Carson, K., Williams, H.M., Karanam, S., Newby, A.C., Angelini, G.D., George, S.J., Jackson, C.L., 2005a. Plaque rupture after short periods of fat-feeding in the apolipoprotein E knockout mouse: model characterisation, and effects of pravastatin treatment. Circulation 111, 1422–1430. Johnson, J.L., George, S.J., Newby, A.C., Jackson, C.L., 2005b. Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc. Natl. Acad. Sci. U. S. A. 102, 15575–15580. Johnson, J.L., Baker, A.H., Oka, K., Chan, L., Newby, A.C., Jackson, C.L., George, S.J., 2006a. Suppression of atherosclerotic plaque progression and instability by tissue inhibitor of metalloproteinase-2: involvement of macrophage migration and apoptosis. Circulation 113, 2435–2444.

Johnson, J.L., Fritsche-Danielson, R., Behrendt, M., Westin-Eriksson, A., Wennbo, H., Herslof, M., Elebring, M., George, S.J., McPheat, W.L., Jackson, C.L., 2006b. Effect of broad-spectrum matrix metalloproteinase inhibition on atherosclerotic plaque stability. Cardiovasc. Res. 71, 586–595. Johnson, J.L., Sala-Newby, G.B., Ismail, Y., Aguilera, C.M., Newby, A.C., 2008. Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages. Arterioscler. Thromb. Vasc. Biol. 28, 1647–1653. Johnson, J.L., Devel, L., Czarny, B., George, S.J., Jackson, C.L., Rogakos, V., Beau, F., Yiotakis, A., Newby, A.C., Dive, V., 2011a. A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein Eknockout mice. Arterioscler. Thromb. Vasc. Biol. 31, 528–535. Johnson, J.L., Dwivedi, A., Somerville, M., George, S.J., Newby, A.C., 2011b. Matrix metalloproteinase (MMP)-3 activates MMP-9 mediated vascular smooth muscle cell migration and neointima formation in mice. Arterioscler. Thromb. Vasc. Biol. 31, e35–e44. Kadl, A., Meher, A.K., Sharma, P.R., Lee, M.Y., Doran, A.C., Johnstone, S.R., Elliott, M.R., Gruber, F., Han, J., Chen, W., Kensler, T., Ravichandran, K.S., Isakson, B.E., Wamhoff, B.R., Leitinger, N., 2010. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ. Res. 107, 737–746. Kubo, T., Imanishi, T., Takarada, S., Kuroi, A., Ueno, S., Yamano, T., Tanimoto, T., Matsuo, Y., Masho, T., Kitabata, H., Tsuda, K., Tomobuchi, Y., Akasaka, T., 2007. Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J. Am. Coll. Cardiol. 50, 933–939. Kuzuya, M., Kanda, S., Sasaki, T., Tamaya-Mori, N., Cheng, X.W., Itoh, T., Itohara, S., Iguchi, A., 2003. Deficiency of gelatinase A suppresses smooth muscle cell invasion and development of experimental intimal hyperplasia. Circulation 108, 1375–1381. Kuzuya, M., Nakamura, K., Sasaki, T., Wu Cheng, X., Itohara, S., Iguchi, A., 2006. Effect of MMP-2 deficiency on atherosclerotic lesion formation in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 26, 1120–1125. Lafleur, M.A., Hollenberg, M.D., Atkinson, S.J., Knauper, V., Murphy, G., Edwards, D.R., 2001. Activation of pro-(matrix metalloproteinase-2) (pro-MMP-2) by thrombin is membrane-type-MMP-dependent in human umbilical vein endothelial cells and generates a distinct 63 kDa active species. Biochem. J. 357, 107–115. Lagente, V., Boichot, E., 2010. Role of matrix metalloproteinases in the inflammatory process of respiratory diseases. J. Mol. Cell. Cardiol. 48, 440–444. Laxton, R.C., Hu, Y., Duchene, J., Zhang, F., Zhang, Z., Leung, K.Y., Xiao, Q., Scotland, R.S., Hodgkinson, C.P., Smith, K., Willeit, J., Lopez-Otin, C., Simpson, I.A., Kiechl, S., Ahluwalia, A., Xu, Q., Ye, S., 2009. A role of matrix metalloproteinase-8 in atherosclerosis. Circ. Res. 105, 921–929. Lemaitre, V., O'Byrne, T.K., Borczuk, A.C., Okada, Y., Tall, A.R., D'Armiento, J., 2001. ApoE knockout mice expressing human matrix metalloproteinase-1 in macrophages have less advanced atherosclerosis. J. Clin. Invest. 107, 1227–1234. Lemaitre, V., Soloway, P.D., D'Armiento, J., 2003. Increased medial degradation with pseudo-aneurysm formation in apolipoprotein E-knockout mice deficient in tissue inhibitor of metalloproteinases-1. Circulation 107, 333–338. Li, A.H., Dubey, S., Varney, M.L., Dave, B.J., Singh, R.K., 2003. IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J. Immunol. 170, 3369–3376. Li, Z., Clarke, M.P., Barker, M.D., McKie, N., 2005. TIMP3 mutation in Sorsby's fundus dystrophy: molecular insights. Expert Rev. Mol. Med. 7, 1–15. Liang, J., Liu, E., Yu, Y., Kitajima, S., Koike, T., Jin, Y., Morimoto, M., Hatakeyama, K., Asada, Y., Watanabe, T., Sasaguri, Y., Watanabe, S., Fan, J., 2006. Macrophage metalloelastase accelerates the progression of atherosclerosis in transgenic rabbits. Circulation 113, 1993–2001. Lindeman, J.H., Abdul-Hussien, H., van Bockel, J.H., Wolterbeek, R., Kleemann, R., 2009. Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells. Circulation 119, 2209–2216. Linder, S., 2007. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol. 17, 107–117. Lindsay, M.E., Dietz, H.C., 2011. Lessons on the pathogenesis of aneurysm from heritable conditions. Nature 473, 308–316. Liu, J., Xiong, W., Baca-Regen, L., Nagase, H., Baxter, B.T., 2003. Mechanism of inhibition of matrix metalloproteinase-2 expression by doxycycline in human aortic smooth muscle cells. J. Vasc. Surg. 38, 1376–1383. Lizarbe, T.R., Tarin, C., Gomez, M., Lavin, B., Aracil, E., Orte, L.M., Zaragoza, C., 2009. Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN. Am. J. Pathol. 175, 1421–1430. Longo, G.M., Xiong, W., Greiner, T.C., Zhao, Y., Fiotti, N., Baxter, B.T., 2002. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J. Clin. Invest. 110, 625–632. Longo, G.M., Buda, S.J., Fiotta, N., Xiong, W., Griener, T., Shapiro, S., Baxter, B.T., 2005. MMP-12 has a role in abdominal aortic aneurysms in mice. Surgery 137, 457–462. Luan, Z., Chase, A.J., Newby, A.C., 2003. Statins inhibit secretion of metalloproteinases1, -2, -3, and -9 from vascular smooth muscle cells and macrophages. Arterioscler. Thromb. Vasc. Biol. 23, 769–775. Luttun, A., Lutgens, E., Manderveld, A., Maris, K., Collen, D., Carmeliet, P., Moons, L., 2004. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 109, 1408–1414. Mach, F., Schonbeck, U., Fabunmi, R.P., Murphy, C., Atkinson, E., Bonnefoy, J.Y., Graber, P., Libby, P., 1999. T lymphocytes induce endothelial cell matrix metalloproteinase expression by a CD40L-dependent mechanism — implications for tubule formation. Am. J. Pathol. 154, 229–238.

Mandriota, S.J., Seghezzi, G., Vassalli, J.D., Ferrara, N., Wasi, S., Mazzieri, R., Mignatti, P., Pepper, M.S., 1995. Vascular endothelial growth-factor increases urokinase receptor expression in vascular endothelial-cells. J. Biol. Chem. 270, 9709–9716. Manicone, A.M., McGuire, J.K., 2008. Matrix metalloproteinases as modulators of inflammation. Semin. Cell Dev. Biol. 19, 34–41. Manning, M.W., Cassis, L.A., Daugherty, A., 2003. Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 23, 483–488. Mao, D., Lee, J.K., VanVickle, S.J., Thompson, R.W., 1999. Expression of collagenase-3 (MMP-13) in human abdominal aortic aneurysms and vascular smooth muscle cells in culture. Biochem. Biophys. Res. Commun. 261, 904–910. Marx, N., Froehlich, J., Siam, L., Ittner, J., Wierse, G., Schmidt, A., Scharnagl, H., Hombach, V., Koenig, W., 2003. Antidiabetic PPAR{gamma}-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 23, 283–288. Monaco, C., Gregan, S.M., Navin, T.J., Foxwell, B.M., Davies, A.H., Feldmann, M., 2009. Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. Circulation 120, 2462–2469. Montero, I., Orbe, J., Varo, N., Beloqui, O., Monreal, J.I., Rodriguez, J.A., Diez, J., Libby, P., Paramo, J.A., 2006. C-reactive protein induces matrix metalloproteinase-1 and −10 in human endothelial cells: implications for clinical and subclinical atherosclerosis. J. Am. Coll. Cardiol. 47, 1369–1378. Moore, G., Liao, S., Curci, J.A., Starcher, B.C., Martin, R.L., Hendricks, R.T., Chen, J.J., Thompson, R.W., 1999. Suppression of experimental abdominal aortic aneurysms by systemic treatment with a hydroxamate-based matrix metalloproteinase inhibitor (RS 132908). J. Vasc. Surg. 29, 522–532. Mosorin, M., Juvonen, J., Biancari, F., Satta, J., Surcel, H.M., Leinonen, M., Saikku, P., Juvonen, T., 2001. Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: a randomized, double-blind, placebo-controlled pilot study. J. Vasc. Surg. 34, 606–610. Musso, O., Theret, N., Campion, J.P., Turlin, B., Milani, S., Grappone, C., Clement, B., 1997. In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. J. Hepatol. 26, 593–605. Nagase, H., Visse, R., Murphy, G., 2006. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 69, 562–573. Nagashima, Y., Hasegawa, S., Koshikawa, N., Taki, A., Ichikawa, Y., Kitamura, H., Misugi, K., Kihira, Y., Matuo, Y., Yasumitsu, H., Miyazaki, K., 1997. Expression of matrilysin in vascular endothelial cells adjacent to matrilysin-producing tumors. Int. J. Cancer 72, 441–445. Nagel, S., Heinemann, P.V., Heiland, S., Koziol, J., Gardner, H., Wagner, S., 2010. Selective MMP-inhibition with Ro 28-2653 in acute experimental stroke—a magnetic resonance imaging efficacy study. Brain Res. 1368, 264–270. Newby, A.C., 2005. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol. Rev. 85, 1–31. Newby, A.C., 2006. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc. Res. 69, 614–624. Newby, A.C., 2008. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler. Thromb. Vasc. Biol. 28, 2108–2114. Nollendorfs, A., Greiner, T.C., Nagase, H., Baxter, B.T., 2001. The expression and localization of membrane type-1 matrix metalloproteinase in human abdominal aortic aneurysms. J. Vasc. Surg. 34, 316–322. Nordon, I.M., Hinchliffe, R.J., Loftus, I.M., Thompson, M.M., 2011. Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat. Rev. Cardiol. 8, 92–102. Oh, J., Takahashi, R., Kondo, S., Mizoguchi, A., Adachi, E., Sasahara, R.M., Nishimura, S., Imamura, Y., Kitayama, H., Alexander, D.B., Ide, C., Horan, T.P., Arakawa, T., Yoshida, H., Nishikawa, S.I., Itoh, Y., Seiki, M., Itohara, S., Takahashi, C., Noda, M., 2001. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107, 789–800. Oh, J., Seo, D.W., Diaz, T., Wei, B.Y., Ward, Y., Ray, J.M., Morioka, Y., Shi, S.L., Kitayama, H., Takahashi, C., Noda, M., Stetler-Stevenson, W.G., 2004. Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK. Cancer Res. 64, 9062–9069. Page-McCaw, A., Ewald, A.J., Werb, Z., 2007. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 8, 221–233. Papalambros, E., Sigala, F., Georgopoulos, S., Menekakos, C., Giatromanolaki, A., Bastounis, E., Sivridis, E., 2003. Immunohistochemical expression of metalloproteinases MMP-2 and MMP-9 in abdominal aortic aneurysms: correlation with symptoms and aortic diameter. Int. J. Mol. Med. 12, 965–968. Parks, W.C., Wilson, C.L., Lopez-Boado, Y.S., 2004. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617–629. Participants, T.U.S.A.T., 1998. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small Aneurysm Trial Participants. Lancet 352, 1649–1655. Partridge, C.R., Hawker, J.R., Forough, R., 2000. Overexpression of a secretory form of FGF-1 promotes MMP-1-mediated endothelial cell migration. J. Cell. Biochem. 78, 487–499. Paulson, K.E., Zhu, S.N., Chen, M., Nurmohamed, S., Jongstra-Bilen, J., Cybulsky, M.I., 2010. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ. Res. 106, 383–390. Peracchia, F., Tamburro, A., Prontera, C., Mariani, B., Rotilio, D., 1997. CAMP involvement in the expression of MMP-2 and MT-MMP1 metalloproteinases in human endothelial cells. Arterioscler. Thromb. Vasc. Biol. 17, 3185–3190.

243

Petersen, E., Gineitis, A., Wagberg, F., Angquist, K.A., 2000. Activity of matrix metalloproteinase-2 and -9 in abdominal aortic aneurysms. Relation to size and rupture. Eur. J. Vasc. Endovasc. Surg. 20, 457–461. Peterson, J.T., 2006. The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. Cardiovasc. Res. 69, 677–687. Petrinec, D., Liao, S., Holmes, D.R., Reilly, J.M., Parks, W.C., Thompson, R.W., 1996. Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: preservation of aortic elastin associated with suppressed production of 92 kD gelatinase. J. Vasc. Surg. 23, 336–346. Plaisier, M., Kapiteijn, K., Koolwijk, P., Fijten, C., Hanemaaijer, R., Grimbergen, J.M., Mulder-Stapel, A., Quax, P.H., Helmerhorst, F.M., van Hinsbergh, V.W., 2004. Involvement of membrane-type matrix metalloproteinases (MT-MMPs) in capillary tube formation by human endometrial microvascular endothelial cells: role of MT3-MMP. J. Clin. Endocrinol. Metab. 89, 5828–5836. Polette, M., Clavel, C., Birembaut, P., Declerck, Y.A., 1993. Localization by in-situ hybridization of messenger-Rnas encoding stromelysin-3 and tissue inhibitors of metallo-proteinases Timp-1 and Timp-2 in human head and neck carcinomas. Pathol. Res. Pract. 189, 1052–1057. Prall, A.K., Longo, G.M., Mayhan, W.G., Waltke, E.A., Fleckten, B., Thompson, R.W., Baxter, B.T., 2002. Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice. J. Vasc. Surg. 35, 923–929. Prescott, M.F., Sawyer, W.K., Von Linden-Reed, J., Jeune, M., Chou, M., Caplan, S.L., Jeng, A.Y., 1999. Effect of matrix metalloproteinase inhibition on progression of atherosclerosis and aneurysm in LDL receptor-deficient mice overexpressing MMP-3, MMP-12, and MMP13 and on restenosis in rats after balloon injury. Ann. N. Y. Acad. Sci. 878, 179–190. Puyraimond, A., Fridman, R., Lemesle, M., Arbeille, B., Menashi, S., 2001. MMP-2 colocalizes with caveolae on the surface of endothelial cells. Exp. Cell Res. 262, 28–36. Pyo, R., Lee, J.K., Shipley, J.M., Curci, J.A., Mao, D., Ziporin, S.J., Ennis, T.L., Shapiro, S.D., Senior, R.M., Thompson, R.W., 2000. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J. Clin. Invest. 105, 1641–1649. Qi, J.H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., Anand-Apte, B., 2003. A novel function for tissue inhibitor of metalloproteinases3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat. Med. 9, 407–415. Quillard, T., Tesmenitsky, Y., Croce, K., Travers, R., Shvartz, E., Koskinas, K.C., Sukhova, G.K., Aikawa, E., Aikawa, M., Libby, P., 2011. Selective inhibition of matrix metalloproteinase-13 increases collagen content of established mouse atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 2464–2472. Rajavashisth, T.B., Liao, J.K., Galis, Z.S., Tripathi, S., Laufs, U., Tripathi, J., Chai, N.N., Xu, X.P., Jovinge, S., Shah, P.K., Libby, P., 1999. Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase. J. Biol. Chem. 274, 11924–11929. Reel, B., Oktay, G., Ozkal, S., Islekel, H., Ozer, E., Ozsarlak-Sozer, G., Cavdar, Z., Akhisaroglu, S.T., Kerry, Z., 2009. MMP-2 and MMP-9 alteration in response to collaring in rabbits: the effects of endothelin receptor antagonism. J. Cardiovasc. Pharmacol. Ther. 14, 292–301. Reel, B., Sala-Newby, G.B., Huang, W.-C., Newby, A.C., 2011. Diverse patterns of cyclooxygenase-independent metalloproteinase gene regulation in human monocytes. Br. J. Pharmacol. 163, 1679–1690. Reeps, C., Essler, M., Pelisek, J., Seidl, S., Eckstein, H.H., Krause, B.J., 2008. Increased 18Ffluorodeoxyglucose uptake in abdominal aortic aneurysms in positron emission/ computed tomography is associated with inflammation, aortic wall instability, and acute symptoms. J. Vasc. Surg. 48, 417–423 discussion 424. Rouis, M., Adamy, C., Duverger, N., Lesnik, P., Horellou, P., Moreau, M., Emmanuel, F., Caillard, J.M., Laplaud, P.M., Dachet, C., Chapman, M.J., 1999. Adenovirus-mediate overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E deficient mice. Circulation 100, 533–540. Rubino, M.T., Agamennone, M., Campestre, C., Campiglia, P., Cremasco, V., Faccio, R., Laghezza, A., Loiodice, F., Maggi, D., Panza, E., Rossello, A., Tortorella, P., 2011. Biphenyl sulfonylamino methyl bisphosphonic acids as inhibitors of matrix metalloproteinases and bone resorption. ChemMedChem 6, 1258–1268. Saito, S., Zempo, N., Yamashita, A., Takenaka, H., Fujioka, K., Esato, K., 2002. Matrix metalloproteinase expressions in arteriosclerotic aneurysmal disease. Vasc. Endovascular Surg. 36, 1–7. Sakalihasan, N., Delvenne, P., Nusgens, B.V., Limet, R., Lapiere, C.M., 1996. Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms. J. Vasc. Surg. 24, 127–133. Sapadin, A.N., Fleischmajer, R., 2006. Tetracyclines: nonantibiotic properties and their clinical implications. J. Am. Acad. Dermatol. 54, 258–265. Schleef, R.R., Bevilacqua, M.P., Sawdey, M., Gimbrone, M.A., Loskutoff, D.J., 1988. Cytokine activation of vascular endothelium — effects on tissue-type plasminogen-activator and type-1 plasminogen-activator inhibitor. J. Biol. Chem. 263, 5797–5803. Schneider, F., Sukhova, G.K., Aikawa, M., Canner, J., Gerdes, N., Tang, S.M., Shi, G.P., Apte, S.S., Libby, P., 2008. Matrix-metalloproteinase-14 deficiency in bone-marrow-derived cells promotes collagen accumulation in mouse atherosclerotic plaques. Circulation 117, 931–939. Sheth, R.A., Maricevich, M., Mahmood, U., 2010. In vivo optical molecular imaging of matrix metalloproteinase activity in abdominal aortic aneurysms correlates with treatment effects on growth rate. Atherosclerosis 212, 181–187. Shimizu, K., Shichiri, M., Libby, P., Lee, R.T., Mitchell, R.N., 2004. Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas. J. Clin. Invest. 114, 300–308. Sho, E., Chu, J., Sho, M., Fernandes, B., Judd, D., Ganesan, P., Kimura, H., Dalman, R.L., 2004. Continuous periaortic infusion improves doxycycline efficacy in experimental aortic aneurysms. J. Vasc. Surg. 39, 1312–1321.

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Silence, J., Lupu, F., Collen, D., Lijnen, H.R., 2001. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler. Thromb. Vasc. Biol. 21, 1440–1445. Silence, J., Collen, D., Lijnen, H.R., 2002. Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ. Res. 90, 897–903. Sluijter, J.P., Pulskens, W.P., Schoneveld, A.H., Velema, E., Strijder, C.F., Moll, F., de Vries, J.P., Verheijen, J., Hanemaaijer, R., de Kleijn, D.P., Pasterkamp, G., 2006. Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms. Stroke 37, 235–239. Sood, R.R., Taheri, S., Candelario-Jalil, E., Estrada, E.Y., Rosenberg, G.A., 2008. Early beneficial effect of matrix metalloproteinase inhibition on blood–brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. J. Cereb. Blood Flow Metab. 28, 431–438. Southgate, K.M., Mehta, D., Izzat, M.B., Newby, A.C., Angelini, G.D., 1999. Increased secretion of basement membrane degrading metalloproteinases in pig saphenous vein into carotid artery interposition grafts. Arterioscler. Thromb. Vasc. Biol. 19, 1640–1649. Stetler-Stevenson, W.G., 2008. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci. Signal. 1, re6. Sukhova, G.K., Schonbeck, U., Rabkin, E., Schoen, F.J., Poole, A.R., Billinghurst, R.C., Libby, P., 1999. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 99, 2503–2509. Takahashi, K., Ikura, M., Habashita, H., Nishizaki, M., Sugiura, T., Yamamoto, S., Nakatani, S., Ogawa, K., Ohno, H., Nakai, H., Toda, M., 2005. Novel matrix metalloproteinase inhibitors: generation of lead compounds by the in silico fragment-based approach. Bioorg. Med. Chem. 13, 4527–4543. Tedesco, M.M., Terashima, M., Blankenberg, F.G., Levashova, Z., Spin, J.M., Backer, M.V., Backer, J.M., Sho, M., Sho, E., McConnell, M.V., Dalman, R.L., 2009. Analysis of in situ and ex vivo vascular endothelial growth factor receptor expression during experimental aortic aneurysm progression. Arterioscler. Thromb. Vasc. Biol. 29, 1452–1457. Tedgui, A., Mallat, Z., 2006. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol. Rev. 86, 515–581. Thomas, A.C., Sala-Newby, G.B., Ismail, Y., Johnson, J.L., Pasterkamp, G., Newby, A.C., 2007. Genomics of foam cells and nonfoamy macrophages from rabbits identifies arginase-I as a differential regulator of nitric oxide production. Arterioscler. Thromb. Vasc. Biol. 27, 571–577. Thompson, R.W., Baxter, B.T., 1999. MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial. Ann. N. Y. Acad. Sci. 878, 159–178. Thompson, M., Cockerill, G., 2006. Matrix metalloproteinase-2: the forgotten enzyme in aneurysm pathogenesis. Ann. N. Y. Acad. Sci. 1085, 170–174. Thompson, R.W., Holmes, D.R., Mertens, R.A., Liao, S., Botney, M.D., Mecham, R.P., Welgus, H.G., Parks, W.C., 1995. Production and localization of 92-kilodalton gelatinase in abdominal aortic aneurysms. An elastolytic metalloproteinase expressed by aneurysm-infiltrating macrophages. J. Clin. Invest. 96, 318–326. Treharne, G.D., Boyle, J.R., Goodall, S., Loftus, I.M., Bell, P.R., Thompson, M.M., 1999. Marimastat inhibits elastin degradation and matrix metalloproteinase 2 activity in a model of aneurysm disease. Br. J. Surg. 86, 1053–1058. Tromp, G., Gatalica, Z., Skunca, M., Berguer, R., Siegel, T., Kline, R.A., Kuivaniemi, H., 2004. Elevated expression of matrix metalloproteinase-13 in abdominal aortic aneurysms. Ann. Vasc. Surg. 18, 414–420. Turner, G.H., Olzinski, A.R., Bernard, R.E., Aravindhan, K., Karr, H.W., Mirabile, R.C., Willette, R.N., Gough, P.J., Jucker, B.M., 2008. In vivo serial assessment of aortic aneurysm formation in apolipoprotein E-deficient mice via MRI. Circ. Cardiovasc. Imaging 1, 220–226. van Hinsbergh, V.W., Koolwijk, P., 2008. Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc. Res. 78, 203–212. Viemann, D., Goebeler, M., Schmid, S., Nordhues, U., Klimmek, K., Sorg, C., Roth, J., 2006. TNF induces distinct gene expression programs in microvascular and macrovascular human endothelial cells. J. Leukoc. Biol. 80, 174–185. Vinh, A., Gaspari, T.A., Liu, H.B., Dousha, L.F., Widdop, R.E., Dear, A.E., 2008. A novel histone deacetylase inhibitor reduces abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice. J. Vasc. Res. 45, 143–152. Virmani, R., Kolodgie, F.D., Burke, A.P., Farb, A., Schwartz, S.M., 2000. Lessons from sudden coronary death — a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 20, 1262–1275.

Virmani, R., Burke, A.P., Farb, A., Kolodgie, F.D., 2006. Pathology of the vulnerable plaque. J. Am. Coll. Cardiol. 47, C13–C18. Visse, R., Nagase, H., 2003. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure function and biochemistry. Circ. Res. 92, 827–839. Wang, H., Keiser, J.A., 2000. Hepatocyte growth factor enhances MMP activity in human endothelial cells. Biochem. Biophys. Res. Commun. 272, 900–905. Wang, B.-W., Chang, H., Lin, S., Kuan, P., Shyu, K.-G., 2003. Induction of matrix metalloproteinases-14 and -2 by cyclical mechanical stretch is mediated by tumor necrosis factor-{alpha} in cultured human umbilical vein endothelial cells. Cardiovasc. Res. 59, 460–469. Wang, J., Taba, Y., Pang, J., Yin, G., Yan, C., Berk, B.C., 2009. GIT1 mediates VEGF-induced podosome formation in endothelial cells: critical role for PLC{gamma}. Arterioscler. Thromb. Vasc. Biol. 29, 202–208. Wang, Y., Ait-Oufella, H., Herbin, O., Bonnin, P., Ramkhelawon, B., Taleb, S., Huang, J., Offenstadt, G., Combadiere, C., Renia, L., Johnson, J.L., Tharaux, P.L., Tedgui, A., Mallat, Z., 2010. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J. Clin. Invest. 120, 422–432. Wesselman, J.P.M., Kuijs, R., Hermans, J.J.R., Janssen, G.M.J., Fazzi, G.E., van Essen, H., Evelo, C.T.A., Struijker-Boudier, H.A.J., De Mey, J.G.R., 2004. Role of the Rhoa/Rho kinase system in flow-related remodeling of rat mesenteric small arteries in vivo. J. Vasc. Res. 41, 277–290. Whalen, A.M., Chen, X.L., Qiu, F.H., Cook, C.K., Sinibaldi, D., Thomas, S., Varner, S.E., Rao, A.S., Wasserman, M.A., Medford, R.M., 2003. Global gene expression analysis of flow-conditioned endothelial cells: oscillatory flow induces a unique set of proinflammatory genes. FASEB J. 17, A274-A274. White, S.J., Hayes, E., Newby, A.C., Unpublished data. Williams, H., Johnson, J.L., Jackson, C.L., White, S.J., George, S.J., 2010. MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis. Cardiovasc. Res. 87, 137–146. Wilson, W.R., Schwalbe, E.C., Jones, J.L., Bell, P.R., Thompson, M.M., 2005. Matrix metalloproteinase 8 (neutrophil collagenase) in the pathogenesis of abdominal aortic aneurysm. Br. J. Surg. 92, 828–833. Wilson, W.R., Anderton, M., Schwalbe, E.C., Jones, J.L., Furness, P.N., Bell, P.R., Thompson, M.M., 2006. Matrix metalloproteinase-8 and -9 are increased at the site of abdominal aortic aneurysm rupture. Circulation 113, 438–445. Xiong, W., Knispel, R., Mactaggart, J., Baxter, B.T., 2006. Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation. J. Vasc. Surg. 44, 1061–1066. Xiong, W., Knispel, R.A., Dietz, H.C., Ramirez, F., Baxter, B.T., 2008. Doxycycline delays aneurysm rupture in a mouse model of Marfan syndrome. J. Vasc. Surg. 47, 166–172 discussion 172. Xiong, W., Knispel, R., MacTaggart, J., Greiner, T.C., Weiss, S.J., Baxter, B.T., 2009. Membrane-type 1 matrix metalloproteinase regulates macrophage-dependent elastolytic activity and aneurysm formation in vivo. J. Biol. Chem. 284, 1765–1771. Yamashita, A., Noma, T., Nakazawa, A., Saito, S., Fujioka, K., Zempo, N., Esato, K., 2001. Enhanced expression of matrix metalloproteinase-9 in abdominal aortic aneurysms. World J. Surg. 25, 259–265. Yana, I., Sagara, H., Takaki, S., Takatsu, K., Nakamura, K., Nakao, K., Katsuki, M., Taniguchi, S.-i., Aoki, T., Sato, H., Weiss, S.J., Seiki, M., 2007. Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells. J. Cell Sci. 120, 1607–1614. Yang, H.H., Kim, J.M., Chum, E., van Breemen, C., Chung, A.W., 2010. Effectiveness of combination of losartan potassium and doxycycline versus single-drug treatments in the secondary prevention of thoracic aortic aneurysm in Marfan syndrome. J. Thorac. Cardiovasc. Surg. 140 (305–312), e302. Yoshimura, K., Aoki, H., Ikeda, Y., Fujii, K., Akiyama, N., Furutani, A., Hoshii, Y., Tanaka, N., Ricci, R., Ishihara, T., Esato, K., Hamano, K., Matsuzaki, M., 2005. Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase. Nat. Med. 11, 1330–1338. Yun, S., Dardik, A., Haga, M., Yamashita, A., Yamaguchi, S., Koh, Y., Madri, J.A., Sumpio, B.E., 2002. Transcription factor Sp1 phosphorylation induced by shear stress inhibits membrane type 1-matrix metalloproteinase expression in endothelium. J. Biol. Chem. 277, 34808–34814. Zempo, N., Koyama, N., Kenagy, R.D., Lea, H.J., Clowes, A.W., 1996. Regulation of vascular smooth muscle cell migration and proliferation in vitro and in injured rat arteries by a synthetic matrix metalloproteinase inhibitor. Arterioscler. Thromb. Vasc. Biol. 16, 28–33.