Published online before print September 4, 2008, doi: 10.1161/ATVBAHA.108.173898
© 2008 American Heart Association, Inc.
Brief Reviews |
Metalloproteinase Expression in Monocytes and Macrophages and its Relationship to Atherosclerotic Plaque Instability
From the Bristol Heart Institute, University of Bristol, UK.
Correspondence to Prof Andrew C. Newby, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E-mail A.Newby{at}bris.ac.uk
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Abstract |
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 Top Abstract IntroductionRegulation of MMP and...Effects of Monocyte and...Final Conclusions and...References |
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Matrix metalloproteinases (MMPs) can degrade strength-giving collagens and other structural proteins of the arterial extracellular matrix. Overproduction of MMPs by monocyte/macrophages could therefore promote atherosclerotic plaque rupture and myocardial infarction. Freshly-recruited monocyte macrophages appear to use a prostaglandin (PG)-dependent pathway to coordinately upregulate a broad and potentially highly-destructive spectrum of MMPs. Differentiated macrophages rely on a series of distinct pathways to selectively upregulate groups of MMPs. Moreover, recent evidence suggests that different macrophage phenotypes express characteristically different spectra of MMPs and their inhibitors. New therapies may result from targeting matrix MMP overproduction.
Overproduction of matrix metalloproteinases from macrophages plays a role in plaque rupture and myocardial infarction. Freshly recruited monocytes use a PG-dependent pathway to coordinately upregulate a highly destructive spectrum of MMPs. Resident macrophages rely on a series of pathways, including activation of nuclear factor 
B, to achieve graded upregulation of MMPs.
Key Words: atherosclerosis • inflammation • proteolysis • gene regulation
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Introduction |
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TopAbstractIntroductionRegulation of MMP and...Effects of Monocyte and...Final Conclusions and...References |
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Destruction of the arterial extracellular matrix (ECM) is an important contributory cause of atherosclerotic plaque rupture, which underlies most cases of myocardial infarction.1 Net loss of collagen, which normally provides the main tensile strength of the artery wall, closely colocalizes with areas of activated foam-cell macrophages especially at so-called "shoulder regions."2 Advanced plaques show large lipid cores in which macrophages are often present and the ECM has been extensively degraded. Advanced lesions also have a hypo-cellular fibrous cap probably attributable to death of macrophages and vascular smooth muscle cells (VSMCs). Recent evidence has revealed considerable diversity in the monocyte and macrophage populations in plaques. Two monocytes subsets have been defined, and plaques shown to attract predominantly the more inflammatory phenotype.3 A variety of macrophage phenotypes have also been defined,4 and at least 2 of these (so-called M1 and M2) were recently shown to be present in atherosclerotic plaques.5 Lipopolysaccharide (LPS) and inflammatory cytokines such as tumor necrosis factor (TNF)-
, interleukin (IL)-1β, and interferon (IFN)-
are all believed to induce the M1 macrophage phenotype.4 The alternative, so-called M2, macrophage phenotype is generated in response to cytokines that include IL-4.4 The roles of these different macrophage phenotypes in plaque progression and instability are just beginning to be investigated. Macrophages secrete several classes of neutral extracellular proteases, including serine proteases, cathepsins, and metalloproteinases (MMPs).6 Although these proteases act in concert, for limitations of space, this review focuses on the MMPs. MMPs are a family of some 23 genetically related proteins that share a common Zn2+-based catalytic mechanism.7 MMP activity is increased by transcription of MMP proform genes and activation of proenzymes by proteolytic cascades, often (but not always) mediated by induction of other MMPs.7 Inactivation is largely by binding to endogenous tissue inhibitors of MMPs (TIMPs).7 Collectively MMPs have the ability to completely degrade collagen and most other ECM components7; they also modify other soluble and cell surface proteins, including cytokines and chemokines, leading to regulation of plaque cell behavior including migration proliferation and death.8 The reasons for considering MMPs culprits in plaque rupture are discussed in several recent reviews.6,9,10 Briefly summarized, studies consistently demonstrate colocalization of MMPs with areas of degraded ECM in human plaques. Several, although not all, MMP knockout and TIMP transgenic mice show reduced atherosclerosis progression or generation of more stable plaque phenotypes. Likewise, some but not all molecular genetic analyses associate functional polymorphisms that increase MMP levels with the incidence of myocardial infarction. Furthermore, several biomarker studies show associations between increased plasma MMP levels and acute coronary syndromes. Cell biology experiments identify mechanisms by which excessive MMP production can cause plaque rupture, either directly by destruction of ECM9 or indirectly through actions that promote death of macrophages11 and vascular smooth muscle cell (VSMC).10 On the other hand, controlled ECM remodeling is essential for migration and proliferation of VSMCs, which contributes to fibrous cap thickening and plaque stability. These opposing actions probably limit the potential for preventing plaque rupture by using broad-spectrum MMP inhibitors.12,13 However, selective inhibitors for some MMPs have been designed, and their effects on atherosclerosis are being tested. An alternative strategy we consider here is to inhibit production of those MMPs implicated in plaque rupture.
MMPs can be secreted by all the cells present in the vascular wall,9 but macrophages are of key importance in human plaques. For example, elevated levels of MMPs-1,14–16 -2,17 -3,14,18 -8,19 -9,14,20 -11,21 -12,22 -13,23 -14 (MT1-MMP),24 and -1625 are all found in macrophage-rich regions of human atherosclerotic plaques. Furthermore, MMPs-1, -3, and -8 are colocalized with cleaved collagen,19,23 which suggests that MMPs are not only expressed but also activated. In situ zymography also demonstrates MMP activity in plaques but not normal media.14 MMP-1, -8, -12, -13, and -16 activity is greater in inflamed, lipid-rich atheromas compared to fibrous plaques.19,22,23,25,26 However, MMP-2 has the opposite association,17,26 which implies that VSMCs and ECs rather than macrophages are the predominant source of MMP-2.
TIMP-1 levels are unchanged14 or elevated16 in human atherosclerotic plaques. TIMP-2 is also abundant24 and TIMP-3 is prominent in macrophages in human plaques.27 TIMPs undoubtedly help to prevent uncontrolled ECM degradation in plaques.
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Regulation of MMP and TIMP Expression in Monocytes and Macrophages |
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TopAbstractIntroductionRegulation of MMP and...Effects of Monocyte and...Final Conclusions and...References |
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Peripheral Blood Monocytes and Monocyte Cell Lines
In a qRT-polymerase chain reaction (PCR) screen, human peripheral blood monocytes (HPBM) were shown to express high levels of MMPs-8, -11, -17, -23, and -25, although all except MMP-11 were downregulated after culturing for a few hours in serum.28 MMPs-1, -2, -3, -7, -9, -10, -12, -14, and -19 appear to be coordinately upregulated in HPBM or monocyte cell lines after brief culture on or adhesion to preformed ECM29 or defined ECM components including laminin, collagen, SIKVAV peptide, fibronectin or extracellular MMP inducer (EMMPRIN)28,30–37 (supplemental Table I, available online at http://atvb.ahajournals.org). Binding to platelets enhances the effects of binding to ECM proteins, owing to cooperation between signaling from integrins and P-selectin.31 Binding to activated ECs also stimulates expression of MMPs-9 and -12.36,38
The mechanism for ECM-dependent MMP upregulation is complex (Figure 1), involving cytoskeletal rearrangement, shape change, and upregulation of integrins, all of which promotes adhesion. This in turn triggers induction of cyclooxygenase (COX)-2, synthesis of PG E2 (PGE2), and action of PGE2 at endothelial prostanoid (EP)4 receptors to elevate levels of intracellular 3'-5'cAMP (cAMP). The evidence for this is as follows:
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- Agonists that activate MMP production also cause induction of shape change, adherence, induction of COX-2, and PGE2 production.29,33
- MMP upregulation can be mimicked by adding PGE239,40 or forskolin,41 a direct activator of adenylate cyclase.
- Induction of MMPs may be blocked by integrin-blocking antibodies36 and by COX inhibitors, including selective COX-2 inhibitors,29,33,40 and antagonists at the EP4 receptor.35,41
- MMP upregulation can be mimicked by adding PGE239,40 or forskolin,41 a direct activator of adenylate cyclase.
Other agonists capable of inducing MMPs-1, -3, -9, -12, or -14 in monotyes include S aureus42–44 and bacterial LPS,33,40,45 through Toll-like receptors (TLRs)46 (Figure 1, supplemental Table I). The effects of LPS on MMPs-2, -7, and -13 appear to be substantially smaller (or absent).28,47 Engagement of CD40 and CD40 ligand (CD40L) increases MMP-9 expression,48 whereas TNF- or IL-1β increase expression of MMPs-9 and -12, in human monocytes.35,45,49 All of these agonists are able to activate the transcription factor nuclear factor-B (NF-B), which has in turn been implicated in upregulation of MMPs-1, -3, and -9.50,51 Hence, upregulation of several MMPs in monocytes could be explained by combined activation of the cAMP/PKA pathway and NF-B (Figure 1).
Monocytes express TIMPs-1, -2, -3 and much lesser amounts of TIMP-4.28 Although TIMP-1 levels are increased by LPS, the other TIMPs are not influenced.27,28,33,34,52 TIMP-1 expression is also increased by the antiinflammatory cytokine IL-10.49
The implication is that monocytes migrating into an atherosclerotic plaque across the activated endothelium and then encountering the vascular ECM upregulate a broad spectrum of MMPs, whereas TIMP secretion remains largely unchanged. The resulting MMP activity is presumably required for penetration into the plaque, although this has not yet been demonstrated directly. Studies in vitro demonstrate that MMP-14 promotes monocyte migration across an endothelial monolayer.36,53 Participation of MMP-14 is also the simplest explanation of the observation that TIMP-2 (but not TIMP-1) inhibits migration of THP-1 cells through a synthetic ECM in vitro and reduces macrophage accumulation in atherosclerotic plaques in mice.54 Other evidence implicates MMP-9 in migration of U937 monocytic cells in vitro55 and in migration of dendritic cells in vitro and in vivo.46 Furthermore, recruitment of macrophages into subcutaneous sponges in vivo is reduced in MMP-12–null mice.56 Invasion of monocytes may not entirely depend on MMPs secreted by monocytes; MMPs released by ECs and VSMCs may cooperate (see Figure 1). For example, ECs appear to be the most important source of MMP-14 for intercellular adhesion molecule-1 (ICAM-1)–dependent monocyte transmigration in vitro.53 Given that monocytes secrete relatively low levels of MMP-2,57 most MMP-2 activated by invading monocytes is likely to be derived from the action of MT-MMPs on pro-MMP-2 derived from ECs or VSMCs.
From the spectrum of MMPs expressed, acutely recruited monocyte macrophages appear highly invasive and destructive of the ECM, which supports the idea that endogenous and pharmacological inhibitors of monocyte MMP expression might be valuable therapeutically. Several studies with agents that have pleiotropic inhibitory effects on atherosclerosis are at least consistent with this contention. For example, IL-4, which reduces atherosclerosis in several experimental studies,58 decreases production of MMP-1 and -9 from monocytes.39,43 HDL, which inhibits progression and causes regression of atherosclerosis, also inhibits TNF-–induced MMP-1 production.33 Antiinflammatory cytokines, IL-10, transforming growth factor (TGF)-β, vitamin D3, and retinoic all inhibit atherosclerosis formation in experimental models58 and reduce MMP-9 production from monocytes.39,42,43,45,49 Some of these effects on MMP secretion are directly on the MMP genes,42 whereas others are mediated through inhibition of PG production.39 Indeed, selective inhibition of PGE2 production and action is another possible strategy for plaque stabilization that is being pursued.41 One discordant finding worth emphasizing is that IFN-, which clearly increases atherosclerosis in mouse models,58 reduces production of MMPs-9 and -12 from monocytes.43,52
Differentiation of Monocytes Into Macrophages
Addition of phorbol myristate acetate (PMA), which promotes differentiation of monocytes and monocyte-like cell lines into macrophages,34,37,52 stimulates secretion of MMPs-1, -3, -7, -9, -12, and -14.28,33,34,45,55,57 MMP-2 is upregulated in U93757 but not THP-1 cells.38 Differentiation of HPBM to human monocyte derived macrophages (HMDM) by culturing in serum and by incubation with granulocyte macrophage colony stimulating factor (CSF) (GMCSF) also induces increased production of MMPs-1, -2, -7, -9, -11, -12, and -14,21,28,33,34,45,57 but not MMP-819 (Figure 2, supplemental Table I). During differentiation, inflammatory mediators IL-1β, TNF, or IFN further increase expression of MMPs-1 and -933,48,59 but not MMP-1252 (Figure 2, supplemental Table I); however, these effects of IFN are indirect.48,59
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TIMP-1 levels are increased by differentiation in culture using serum, PMA, or GMCSF,28,33,34,52 whereas TIMP-2 levels appear to decrease.28 TIMP-3 levels decrease in PMA treated THP-1 cells34 but increase during conversion of HPBM to HMDM27 (supplemental Table I).
These findings underline the conclusion that recently recruited monocyte-macrophages are likely to be highly invasive and destructive of the vascular ECM. Further work is needed to address the mechanism underlying MMP upregulation during differentiation so that specific interventions can be devised.
Fully Differentiated Macrophages and Foam Cells
Regulation of MMP production in macrophages appears much less coordinate than for monocytes. Hence it is more logical to deal with regulation of each MMP separately while grouping together those that show similar patterns of regulation.
Constitutive Upregulation Independent of NF-B
The gelatinases MMP-257 and MMP-943,44,47,51,57,59–67 are constitutively expressed in macrophages after differentiation (Figure 2, supplemental Table II). At least in human and rabbit macrophages MMP-9 predominates over MMP-2. Further upregulation of MMP-9 expression by LPS in human macrophages is only modest47,61,63 or even absent57; CD40L and ox-LDL are also ineffective.51,59,67,68 MMP-9 expression is not upregulated in rabbit in vivo generated foam cells compared with nonfoamy macrophages.51 Moreover human macrophage and rabbit foam cell MMP-9 expression is not affected by adenovirus-mediated overexpression of the inhibitory subunit of NF-B, IB.51 MMP-11 is much less studied than MMP-9 but may have a similar patter of expression, because constitutive levels in HMDM are only weakly increased by CD40L.21
Regulated Expression Dependent on NF-B
Despite the abundant evidence detailed above for MMP upregulation during differentiation, HMDM, peritoneal, and alveolar macrophages express low levels of MMPs-1, -3, and -8 under unstimulated conditions (Figure 2, supplemental Table II).29,43,44,47,51,57,63,66,69 MMP-1 is upregulated in macrophages by treatment with ox-LDL, activation of TLRs by bacterial products or the CD40 receptor by CD40L from activated T-lymphocytes.43,44,63,69 These agents are all capable of activating NF-B, and MMP-1 induction is suppressed by overexpressing the inhibitory subunit IB.51 Consistent with this, MMP-1 production from in vivo generated rabbit foam cell macrophages, which constitutively express activated NF-B, is also inhibited by IB.51 Upregulation of MMP-3 is somewhat similar to MMP-1. MMP-3 is upregulated by bacterial LPS in human and rabbit alveolar macrophages57 although LPS, CD40L, TNF- IL-1β, and ox-LDL fail to induce MMP-3 in HMDM.51,63 MMP-3 secretion from in vivo generated rabbit foam cell macrophages is, like MMP-1, inhibited by IB.51 MMP-8 may also fall into this group because it is expressed at low levels in HMDM but is upregulated by LPS, TNF-, IL-1β, and CD40L19 (Figure 2, supplemental Table II). MMP-16 was also induced 3- to 5-fold by macrophage CSF (MCSF), TNF-, and ox-LDL in HMDM.25 Dependency on NF-B is however not yet established for MMP-8 or MMP-16.
Constitutive Expression Strongly Upregulated by IL-4
Constitutive MMP-12 production was further increased by LPS in rat alveolar macrophages and by CD40L, TNF, and IL-1 in HMDM52; MMP-12 was also increased in in vivo derived rabbit foam cells compared with nonfoamy macrophages.70 Constitutive MMP-12 expression is not further upregulated by ox-LDL in HMDM.70 IL-4 is the most potent stimulus for MMP-12 secretion in mouse71 macrophages. This is in strong contrast to the inhibitory effect of IL-4 on MMPs-1 and -9 secretion (see below).
Other Mechanisms
Constitutive MMP-13 was further upregulated by LPS but not by TNF or IL-1β in mouse peritoneal macrophages.61 MMP-14 was upregulated by LPS in human alveolar macrophages62 and by TNF- in HMDM, where the transcription factor serum amyloid A activating factor (SAF)-1 rather than NF-B was implicated.24 MMP-14 expression is increased in a subpopulation of rabbit foam-cell macrophages.11
TIMPs
TIMPs-1, -2, and -3 are constitutively expressed in macrophages.27,51,63,66,67 TIMP-1 is further induced by LPS in HMDM63 and by IL-6 and -10 in human alveolar macrophages.44 Changes in TIMP-2 expression have not been documented, but constitutive expression of TIMPs-1 and -2 is independent of NF-B.51 TIMP-3 expression in HMDM is not increased by LPS27 (Figure 2, supplemental Table II). We recently showed that TIMP-3 is downregulated in rabbit foam cells compared to nonfoamy macrophages.11
In conclusion, differentiation of monocytes into macrophages causes transient upregulation of many MMPs, but only some remain constitutively expressed. More work is needed to understand the function of, and pathways controlling, constitutive production of MMPs-2, -9, and -11, which are expressed at near maximal levels in resting macrophages (Figure 2). MMPs-1, -3, and -8, in particular, are downregulated to very low levels in resident, nonfoamy macrophages, which may therefore be comparatively inert toward intact ECM compared to recently recruited monocytes. Expression of MMP-1 is rapidly upregulated by bacterial products, inflammatory mediators and ox-LDL in a pathway that depends on NF-B (Figure 2). Indeed, conversion of nonfoamy macrophages to foam cells constitutively upregulates NF-B and expression of MMP-1, and this promotes collagen cleavage in vitro51 and in vivo.14,23 The molecular basis for the upregulation of other MMPs in activated macrophages and foam cells is unknown, except for MMP-14, where this is through transcription factor, SAF-1 (Figure 2). The mechanisms responsible for MMP activation in plaques are also imperfectly understood. Protease cascades involving cathepsins, MMPs, and serine proteases have been discussed.9 Reactive oxygen species and nitric oxide can directly activate MMPs,7 and increased production from foam cells macrophages72,73 may therefore contribute.
Inhibiting MMP production from foam cells should have a beneficial effect on plaque stability. Data consistent with this hypothesis are as follows: IL-443 and -1044 inhibit production of MMPs-1 and -9 from human alveolar macrophages (supplemental Table II). Agonists of the nuclear hormone receptors peroxisome proliferator activator receptor (PPAR)65 and liver X receptor (LXR)61 inhibit MMP-9 production from human and mouse macrophages, and LXR agonists also inhibit the production of MMPs-12 and -13.61 Several HMGCoA reductase inhibitors (statins) inhibit MMP-1, -2, -3, and -9 production from human and macrophages and rabbit foam cells derived in vivo.60,64,74 The effects of statins occur at concentrations attainable clinically, appear to be at least partly posttranslational, and are mediated by inhibition of protein prenylation rather than cholesterol starvation.60,74 Contrary data are again obtained with IFN, which inhibits production of MMPs-1,43,69 -3,69 -9,59,61–63 -12,52 -13,61 and -1462 from macrophages. IL-4, IFN, modified LDL, and IL-8 also downregulate expression of TIMP-1 in macrophages,43,63,66,67 which could further increase MMP activity. Effects on the other TIMPs have not been reported. A further interesting conclusion from these studies is that many of the inhibitors act against a broad spectrum of MMPs, independently of the specific mechanism of MMP upregulation detailed above. The basis for this deserves further study. Surprisingly, the effect of PG-related inhibitors appears undocumented in differentiated macrophages and foam cells, despite the extensive literature with monocytes.
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Effects of Monocyte and Macrophage Diversity |
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TopAbstractIntroductionRegulation of MMP and...Effects of Monocyte and...Final Conclusions and...References |
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So far there seems to have been no systematic study of MMP upregulation in the 2 recently defined monocytes phenotypes. Such studies would clearly be worthwhile. There is however evidence of divergent MMP and TIMP expression in subsets of rabbit and human macrophages. Whereas MMPs-1, -3, and -9 appear at all stages of plaque development and are widely distributed within plaques,14,15,18 MMP-11 is found only in advanced atherosclerotic plaques rather than fatty-streaks.21 MMP-7 and lesser amounts of MMP-12 appear confined to the borders between the lipid core and the macrophage-rich shoulder regions of human plaques.22 Similarly, MMP-12 expression is confined to deep macrophages in advanced rabbit atherosclerotic plaques.70 Selective upregulation of MMP-12 by IL-4 and its inhibition by IFN-
is reminiscent of Thelper2 polarization of the immune response, which is associated with the generation of the M2 macrophage phenotype. This regulatory pattern has been associated with aneurysm formation.71 Very recently, we showed that TIMP-3 is downregulated and MMP-14 upregulated in a subpopulation of rabbit and human foam cell macrophages.11 This phenotype was associated with greater degradation of, and invasion through, synthetic ECM, greater proliferation, and greater apoptosis in response to serum-starvation or LPS in vitro. These biochemical properties and localization close to the lipid core suggest that this phenotype might have a preferential role in core formation (through apoptosis) and destruction of the ECM (through MMPs). Macrophages close to the lipid core of advanced rabbit plaques also have low expression of arginase-I,70 which is a phenotypic marker for proinflammatory, M1 macrophages.4 It is therefore tempting to propose that the TIMP-3low, MMP-14high macrophages could be M1 phenotype, but this remains to be established. |
Final Conclusions and Implications |
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TopAbstractIntroductionRegulation of MMP and...Effects of Monocyte and...Final Conclusions and...References |
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Blood monocytes express low levels of a few MMPs28 but cell and matrix contact leads to PGE2 production, stimulation of intracellular cAMP, and rapid upregulation of a broad spectrum of MMPs (Figure 1). Selective inhibitors of PGE2 production or action could therefore be effective plaque stabilizing agents,35,41 especially if plaque rupture is caused by acute episodes of renewed inflammation. LPS, CD40 ligation, and inflammatory cytokines induce additional changes in monocyte MMP expression that, by analogy with macrophages, might be mediated through NF-
B (Figure 1), but this needs to be confirmed directly. Recently recruited monocytes further upregulate MMP secretion during differentiation to macrophages, but it is not yet clear whether PGE2-related mechanisms contribute to this (Figure 2).
Upregulation of several MMPs in fully differentiated macrophages through an NF-B dependent pathway most likely contributes to their destructive power in plaques, where NF-B is continuously activated. Other proinflammatory pathways such as SAF-1 undoubtedly contribute. The effects of IFN- and IL-4 are particularly intriguing. The fact that IFN, which is associated with proinflammatory Thelper1 polarization and the M1 macrophage phenotype, inhibits the secretion of many MMPs from macrophages is an exception to the rule that proinflammatory mediators increase MMP secetion. The upregulation of MMP-12 production in macrophages by IL-4 and its inhibition by IFN- is also intriguing because it suggests an association with Thelper2 polarization and M2 macrophage phenotype. This seems to be selective for MMP-12 because IL-4 and IL-10, which is produced by Thelper2 and regulatory T-cells, inhibit production of many other MMPs (supplemental Table II). These data suggest an interaction between T-cell activation and MMP activity in plaques that deserves further study.
Research summarized in this review has identified a host of physiological and pharmacological inhibitors of MMP production from macrophages, some of which may be useful to prevent plaque rupture. Among the endogenous inhibitors, IL-10 and TGFβ have both been shown to reduce atherosclerosis and promote more stable plaque phenotypes.2 Several drugs commonly used to treat patients with, or at risk from, cardiovascular disease, including statins and PPAR agonists, also inhibit MMP production from macrophages as part of their pleiotropic actions (supplemental Table II). These observations encourage future research into the mechanisms underlying MMP regulation in monocytes and macrophages so as to reveal more direct ways to prevent excessive MMP activity and thereby stabilize vulnerable atherosclerotic plaques.
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Acknowledgments |
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Sources of Funding
The author’s work is supported by the British Heart Foundation and the European Vascular Genomics Network.
Disclosures
None.
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Footnotes |
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Original received December 4, 2007; final version accepted August 25, 2008.
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References |
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TopAbstractIntroductionRegulation of MMP and...Effects of Monocyte and...Final Conclusions and...References |
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