Regulation of matrix metalloproteinase expression

Drug Discovery Today: Disease Models

Vol. 8, No. 1 2011

Editors-in-Chief Jan Tornell – AstraZeneca, Sweden Andrew McCulloch – University of California, SanDiego, USA

DRUG DISCOVERY

TODAY

DISEASE

MODELS

Proteolytic degrading processes in the microcirculation

Regulation of matrix metalloproteinase expression Jennifer L. Gorman, Eric Ispanovic, Tara L. Haas* School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Canada

The matrix metalloproteinases are a family of matrix degrading enzymes that are important regulators of extracellular matrix remodelling and cellular function. This article presents a review of the mechanisms through which MMPs are regulated including transcriptional,

post-transcriptional

and

Section editors: Geert Schmid-Scho¨nbein – University of California San Diego, Department of Bioengineering, Powell-Focht Bioengineering Hall, La Jolla, CA 92093-0412, USA. Herbert Lipowsky – Penn State University, Department of Bioengineering, University Park, PA 16802, USA.

post-translational

events. Regulation of MMPs within the cardiovascular system and their contribution to physiological and pathological events will be discussed.

The matrix metalloproteinases (MMPs) are a family of zinc and calcium dependent endopeptidases known to play important roles in the remodelling of basement membrane and interstitial matrix proteins [1,2]. MMPs (more than 20 in total) may be characterized into the following groups based on common structural elements and proteolytic specificities: matrilysins (MMP-7 and MMP-26), collagenases (MMP-1, MMP-8 and MMP-13), stromelysins (MMP-3, MMP-10 and MMP-11) gelatinases (MMP-2 and MMP-9) and membrane type (MT)-MMPs (MMP-14 (MT1-MMP), MMP-15, MMP-16, MMP-17, MMP-24 and MMP-25) [1,2]. The ADAM (a disintegrin and metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are related families of proteases that also play significant roles in the regulation of physiological and pathophysiological remodelling within the vascular system [3,4]. The current review will focus only on the MMPs. All MMPs are secreted, with the exception of the MT-MMPs, which remain bound to the cell surface by a C-terminal transmembrane domain or *Corresponding author.: T.L. Haas ([email protected]) 1740-6757/$ .Crown Copyright ß 2011 Published by Elsevier Ltd. All rights reserved.

glycophosphatidyl inositol (GPI) anchor. Regulation of MMPs occurs via transcriptional, post-transcriptional and post-translational mechanisms. We will review these regulatory mechanisms and then focus on the physiological and pathological regulation of MMPs within the cardiovascular system, with emphasis on MMP-2, -9 and MT1-MMP.

Transcriptional regulation MMP expression is regulated predominantly through modulation of transcription. Many MMP promoters contain common cis-elements, such as those interacting with transactivators AP-1, NF-kB, PEA3, suggesting coordinated transcription in response to growth factor or cytokine stimulation [5,6]. Various MMPs, including MMP-1, MMP-7, MMP-9, MMP-13 and MT1-MMP, also contain TGFb inhibitory elements that support binding of the SMAD family of transcription factors, resulting in suppressed MMP expression [7]. Unlike most MMPs, both the MMP-2 and MT1-MMP promoters lack both a TATA box and a proximal AP-1 site [8]. Transcription of these MMPs is stimulated by mechanical forces, as well as by growth factors, often utilizing Akt or mitogen activated protein kinase (MAPK) signalling pathways [9]. Under basal conditions, the transcription of both MT1-MMP and MMP-2 is under the control of a GC-rich region within the 50 -promoter [10]. Activity of the MMP-2 promoter is regulated by binding of transcription factors DOI: 10.1016/j.ddmod.2011.06.001

5

Drug Discovery Today: Disease Models | Proteolytic degrading processes in the microcirculation

including Fra-1-Jun B or FosB-Jun B at a non-canonical AP-1 site [5,6]. The responsive element (RE)-1, a cis-element, adjacent to the non-canonical AP-1 site, binds YBox (YB)-1, AP-2 and p53, resulting in enhanced transcription of MMP-2 [11]. Other established transcriptional regulators of MMP-2 include GATA-2 [12] and b-catenin/T Cell Factor (TCF) [13]. Less is known about the transcriptional regulation of MT1-MMP. In endothelial cells, competition between Sp1 and Egr-1 binding to a common GC-rich cis-element controls MT1-MMP expression [10] and regulation of the promoter by b-catenin/TCF also has been reported in endothelial cells and cancer cell lines [13,14].

Post-transcriptional modulation Stability of mRNA is regulated through binding of proteins to A + U elements located in the 30 untranslated region (UTR) of the transcript. The Hu protein family interact with these elements to increase mRNA stability, while other proteins promote degradation through recruitment of mRNA degradation machinery [15]. Modulation of transcript stability has been described for MMP-1, -2, -9, and -13 in response to growth factor or hormonal stimulation [16]. Interestingly, inhibition of HuR expression by nitric oxide increased the decay rate of MMP-9 transcripts [5]. Given the pivotal role of nitric oxide signalling within the vascular system, it would be relevant to examine the effects of nitric oxide on the transcript stability of other MMP family members. More recent work has established the involvement of micro RNAs (miR) in the regulation of gene expression through inhibition of translation and/or modulation of mRNA degradation. Although little is known to date about the effect of miR on MMP expression, both the MMP-2 and MT1-MMP 30 UTRs contain miR binding sites [8]. miR-29b inhibited MMP2 expression in prostate cancer cells [17]. Recently, Roy et al. (2009) reported an indirect role of miR-21 in the modulation of MMP expression following ischemia reperfusion of the heart. miR-21, which was significantly elevated in the cardiac fibroblasts found within the infarct region, downregulated PTEN expression, thus enhancing PI3K/Akt signalling and increased MMP-2 expression [18]. Undoubtedly, continuing research will uncover additional mechanisms through which miR regulate MMP expression.

Post-translation modifications Activation MMPs are produced as inactive zymogens that require proteolytic processing to become active [19]. The pro-domain of all MMPs has a conserved cysteine residue that binds to the zinc ion in the catalytic domain. Disruption of this interaction occurs when the pro-peptide is cleaved or unfolded, allowing substrate access to the catalytic site [20]. Physiological activators of MMPs include plasmin and other MMPs. Activation of MMP-2 typically relies on cell surface interac6

www.drugdiscoverytoday.com

Vol. 8, No. 1 2011

tion with MT1-MMP, utilizing Tissue Inhibitor of Metalloproteinase (TIMP)-2 as a docking module, which exposes the pro-domain of MMP-2 to the catalytic domain of an adjacent MT1-MMP protein, and subsequent cleavage of the prodomain [21,22]. Non-traditional activation of MMP-2 also has been described [23], but there is little evidence to suggest that it is a significant contributor to MMP-2 activation in vivo. MMP-2 and MMP-9 may be activated by serine proteases, such as mast cell chymase [24], which could play a significant role under inflammatory conditions.

Phosphorylation There is evidence that the human MMP-2 gene can be phosphorylated at serine, threonine and tyrosine residues. Phosphorylation of MMP-2 in vitro by protein kinase C decreased its activity [25]. Phosphorylation of the cytoplasmic domain of MT1-MMP also has been reported, although the functional consequence of this phosphorylation is unknown [16]. As the effects of MMP phosphorylation are not well described to date, the physiological significance of phosphorylation in the regulation of MMP expression or activity remains to be established.

Oxidation/nitrosylation Myeloperoxidase is a by-product of oxidative stress and can cause a conformational change within the MMP catalytic domain, yielding an active enzyme [7]. Peroxynitrite also has directly activated MMP-1, -8, -9 and -2 through s-glutathiolation of the pro-peptide cysteine sulfydryl group, which disrupts the Cys–Zn interaction without requiring cleavage of the pro-peptide [16]. Thus, the cellular microenvironment potentially may modify MMP activity independent of changes in enzyme production.

Endogenous inhibitors of MMPs MMP activity is suppressed endogenously by the TIMPs. There are 4 different TIMPs, each of which has differing affinities for various MMPs. TIMPs interact with, and inhibit, MMPs by forming a non-covalent bond via their N-terminal domain [8]. Other proteins also have affected MMP activity. a2-Macroglobulin, thrombospondin (TSP)-1 and TSP-2 are able to interact with some MMPs in the plasma and act to remove them from the extracellular environment, diminishing the overall proteolytic activity [26]. RECK (Reversioninducing cysteine-rich protein with Kazal motifs) is a GPIanchored glycoprotein that is localized to the membrane surface and regulates the activity of MMP-2, MMP-9 and MT1-MMP (and expression of MMP-2) during embryonic development and in cancer cell lines [27].

Physiological and pathological roles of vascular MMPs MMPs cleave a wide range of substrates, including extracellular matrix proteins, cell surface receptors, growth factors,

Vol. 8, No. 1 2011

Drug Discovery Today: Disease Models | Proteolytic degrading processes in the microcirculation

and cytoplasmic proteins. Given this broad range of activity, it is not surprising that MMPs are implicated as significant regulators of many physiological and pathological conditions including embryogenesis, angiogenesis, muscle repair, wound healing, ischemia and/or reperfusion, atherosclerosis and tumor growth. We will focus on the cardiovascularspecific roles of MMPs.

Angiogenesis MMPs play a crucial role in the blood vessel growth stimulated by mechanical factors. Chronic electrical stimulation, or functional overload, of rat skeletal muscle increases both MMP-2 and MT1-MMP mRNA and protein levels [28,29]. In humans, muscle activity increases the production and activity of MMP-9 and MMP-2 [30,31]. Inhibition of MMP activity, using the general MMP inhibitor GM-6001, attenuates the angiogenic response to electrical stimulation [28], indicating a crucial role for MMP activity in the formation of new blood vessels. Both MMP-2 and MT1-MMP are produced by endothelial cells and are able to cleave basement membrane and interstitial matrix proteins. Expression of MMP-2 and MT1-MMP is stimulated by mechanical forces and/or exposure to interstitial matrix proteins, as observed in vitro when cells are cultured in 3D matrices of fibronectin [32] or type I collagen [33]. The increased activity of MMP-2 and MT1MMP correlates with increased sprouting and organization of endothelial cells into chord-like structures [33,34]. Endothelial cell activation by stretch promotes expression of MMP-2, dependent on JNK1/2 activation [35]. MMP expression and activation can be stimulated by angiogenic growth factors, such as vascular endothelial cell growth factor (VEGF). VEGF stimulation of microvascular endothelial cells increases MMP-2 transcription, with key roles for c-Jun, b-catenin and the Rho GTPases in the enhanced transcript levels [13,36,37]. VEGF also promotes rapid cell surface activation of MMP-2, dependent on Rho GTPase activity [36,37]. Interestingly, b-catenin also can trans-activate the c-Jun promoter to induce upregulation of genes that lack b-catenin/TCF binding sites [38], which provides an alternative mechanism through which b-catenin can regulate MMP-2 transcription. VEGF induces MT1-MMP and MMP-10 expression in endothelial cells, dependent upon histone deacetylase 7 (HDAC7) phosphorylation and sequestration in the cytoplasm [39]. Inhibition of HDAC7 phosphorylation blocks VEGF-mediated endothelial cell migration, tube formation, as well as sprouting from aortic ring explants [39]. MMPs modulate the process of angiogenesis both directly and indirectly. MMP cleavage of basement membrane and interstitial matrix components is associated with enhanced endothelial cell sprout formation and elongation [10]. However, cleavage of these proteins can lead to the exposure of matricryptic sites that modulate cell phenotype. For instance,

MMP-2 cleavage of collagen IV makes available a new epitope that interacts with avb3 rather than a1b1 integrin, promoting intracellular signals that activate endothelial cell sprouting and migration [40]. MMP-9 is capable of releasing VEGF165 from extracellular matrix, thus inducing VEGF-dependent angiogenic behaviour [41]. Ectodomain shedding of cell surface receptors such as Tie2 [42] modulates the activation of angiopoeitin-dependent pathways, again affecting endothelial cell phenotype. However, MMP cleavage products also may act to inhibit angiogenesis, perhaps as a feedback mechanism to self-limit an angiogenic response [43].

Vascular remodelling by hemodynamic forces Arteries and veins undergo the adaptive process of outward remodelling in response to prolonged elevation in blood flow. Expression and activity of MT1-MMP and MMP-2 are elevated during outward remodelling of collateral mesenteric arteries, correlating with increased expression of the transcription factors Egr-1 and c-Jun [44]. MT1-MMP and MMP-2 expression can be detected in endothelial, smooth muscle and adventitial cells of the flow-stimulated arterial wall. Inhibition of MMP activity reduces the typical outward luminal remodelling [44]. Wall tension also regulates MMP expression in arteries and veins. MMP-2 promoter activity (but not that of MMP-9) is enhanced in the smooth muscle of isolated aortic rings in response to increased wall tension [45]. Increased wall tension results in elevated expression of MMP2 and -9 in veins, which correlates with a progressive increase in venous dilation that typically are associated with the development of varicose veins [46]. However, shear stress stimulation of microvascular endothelial cells results in decreased expression of MMP-2 and MT1MMP [47,48]. The reduction in MT1-MMP production is linked to a downregulation of Egr-1 in endothelial cells exposed to chronic shear stress, resulting in lower transcriptional activity of the MT1-MMP promoter [43]. Downregulation of MMP-2 expression in response to shear stress depends partly on p38 MAPK signalling and nitric oxide production [48]. Similarly, chronic elevation of capillary shear stress in rat muscles significantly decreases MMP-2 activity [29]. Shear stress also promotes expression of the protease inhibitors TIMPs1,3 and PAI-1 [48]. Considered together, these responses suggest that elevated shear stress in capillaries promotes responses to reduce proteolysis, and thus stabilize capillary wall integrity. Mechanisms underlying the different patterns of responses in large arteries and capillaries remain to be elucidated, though they may be associated with the different cellular components within the respective vessel walls.

Atherosclerosis In atherosclerosis, the loss of extracellular matrix components leads to plaque instability and eventual plaque rupture [49]. Although all cells within the vascular wall can secrete www.drugdiscoverytoday.com

7

Drug Discovery Today: Disease Models | Proteolytic degrading processes in the microcirculation

MMPs, the primary source within the plaque is macrophages. Studies have indicated that monocytes/macrophages enhance MMP production via pathways involving prostaglandins and NF-kB [49]. MMPs also facilitate the release of vascular smooth muscle cells (VSMC) from their interactions with the extracellular matrix, thus promoting VSMC migration and neointima formation [50]. MMP-2 deficiency results in decreased VSMC migration and neointima formation [51], and a reduction in the formation of atherosclerotic lesions in ApoE knockout mice [52]. MMP-9 deficiency also has decreased intimal hyperplasia as well as inhibited smooth muscle cell migration and matrix remodelling, indicating that MMP-9 is important for multiple processes within plaque formation [53]. Recently, it was reported that miR29b is upregulated in vascular smooth muscle cells exposed to oxidized LDL, resulting in demethylation of MMP-2 and MMP-9 genes, which resulted in their enhanced transcription [54]. This study provides novel evidence of epigenetic modulation of MMPs, which may contribute to the development of atherosclerosis.

Hypertension Abnormal elevation in MMP activity is credited with contributing to maladaptive vascular remodelling that occurs in hypertension [55]. Increased basal expression of MMP-2 and MMP-9 also is detected in spontaneously hypertensive rats (SHR) compared with normotensive controls [7]. This may be a result of elevated NF-kB signalling in hypertensive animals, as inhibition of NF-kB was sufficient to inhibit MMP-9 expression [56]. Expression of MMP-2 and MMP-9 in hypertensive patients is reported to both increase and decrease [50], indicating that the state of disease progression may influence detected MMP expression levels. The increased production of these MMPs may contribute to the progression of hypertension. For example, vascular stiffening may result as a consequence of MMP-dependent vascular remodelling. Initially, these events appear beneficial, alleviating the rise in blood pressure [50]. However in the long term, the increased breakdown of matrix components results in an altered balance between collagen and elastin within the arteries, resulting in enhanced stiffness of the arteries [57]. Elevated MMP-2 activity has been associated with endothelial cell dysfunction in hypertensive animals. MMP inhibition restored endothelial cell-dependent dilation of artery segments [57]. Furthermore, in the spontaneously hypertensive rat, MMP-dependent cleavage of b2-adrenergic and VEGFR2 receptors on vascular endothelial cells has contributed to the loss of vasodilatory responses and induction of endothelial cell apoptosis, respectively [58,59], both of which would negatively impact total peripheral resistance. Pre-eclampsia patients also exhibit elevated blood pressure and MMP-mediated vascular remodelling. Consequently, it has been speculated that increased MMP-2 activity may con8

www.drugdiscoverytoday.com

Vol. 8, No. 1 2011

tribute to the endothelial dysfunction that is central to the pathophysiology of pre-eclampsia [60]. This is supported by the observation that MMP-2 levels are elevated in the plasma of women before their diagnosis with pre-eclampsia [61].

Cardiac remodelling MMPs are associated with myocyte hypertrophy as well as with the infiltration of inflammatory cells within damaged myocardium. In response to cardiac pressure overload, left ventricle (LV) functionality initially is maintained within normal limits; however, it then transitions into LV dysfunction. The period of normal functionality is characterized by decreased MMP-1 and MMP-9 levels, while TIMP-2 and -3 levels are elevated. However, increased MMP levels, particularly MMP-2, are observed with the progression to LV dysfunction [7] and the characteristic LV hypertrophic response to pressure overload is blunted in MMP-2 null mice [62]. Volume overload in the heart results in rapid matrix degradation, loss of normal myocyte-matrix support and LV dilation. In response to volume overload, there is a rapid increase in MMP expression and the increase in MMP-2 expression is associated temporally with mast cell density [7]. MMPs also play a role in the damage associated with myocardial infarction (MI). In human MI patients, the infarct area shows increased expression of both MMP-2 and MMP-9 [7]. Induction of MI in MMP-9 null mice results in a reduction in the degree of LV dilation, as well as adverse matrix remodelling. Mice null for either MMP-2 or MMP-9 have reduced macrophage infiltration post MI, correlating with increased recovery of function [7]. Conversely, cardiac restricted overexpression of MT1-MMP decreases left ventricle functionality and leads to significant fibrosis [63], as does MI induction in TIMP-1 null mice [7].

Ischemia or reperfusion injury MMPs play a crucial role in the pathogenesis of ischemia/ reperfusion injury. MMP inhibition blocked the degradation of sarcomeric proteins typically seen following ischemia reperfusion and also decreased other markers of ischemic damage [16], providing evidence of an intracellular proteolytic function of MMPs. However, ischemia-reperfusion also is associated with increased MMP-2 secretion (detectable within the coronary effluent) [7]. Using transgenic mice harbouring rat MMP-2 promoter-reporter DNA constructs, it was ascertained that the increase in MMP-2 expression in response to cardiac ischemia reperfusion resulted from an altered pattern of transcription factor binding to the AP-1 site. While JunB homodimers interacted with the AP-1 site in control animals, this promoter site was occupied by JunBFosB heterodimers following ischemia reperfusion [6]. Hindlimb ischemia also increases MMP-2 mRNA transcript levels and activity. However, deletion of MMP-2 impairs the restoration of perfusion to the ischemic limb [64], suggesting

Vol. 8, No. 1 2011

Drug Discovery Today: Disease Models | Proteolytic degrading processes in the microcirculation

that MMP activity promotes the repair of the ischemic muscle. Ischemia was associated with increased c-Fos, c-Jun, JunB, FosB and Fra 2 expression and binding to the non-canonical AP-1 site of the MMP-2 promoter, together with decreased binding of the transcriptional repressor JunD [64]. p53 binding to the RE-1 site in the MMP-2 promoter also was increased during ischemia. Deletion of the 50 AP-1/RE-1 region abolished ischemia-induced MMP-2 transcription in vivo. MMP-9 / also has reduced recovery post-ischemia, which is associated with reduced infiltration of macrophages/neutrophils, which appear to promote myocyte recovery and to stimulate angiogenesis within the affected region [65,66].

Pharmacological inhibition of MMPs MMP inhibitors (MMPIs) belong to one of four categories: peptidomimetics, nonpeptidomimetics, chemically modified tetracycline derivatives (CMTs) and bisphosphonates (as reviewed in [67,68]). Peptidomimetics mimic the structure of collagen at the site cleaved by MMPs (i.e. marimistat). They chelate zinc at the active site on the MMPs, thus acting as competitive inhibitors. They tend to exhibit broad spectrum inhibition of multiple MMPs. Nonpeptidomimetic MMPIs are designed to complement the three-dimensional conformation of the MMP active site, and as such, have greater specificity to

Growth Factor

sub-groups of MMPs (i.e. BAY12-9566/Tanomastat). However, these drugs also are unable to selectively target an individual MMP. CMTs (such as doxycycline hyclate) interfere with MMP activity by chelation of zinc and calcium ions, but they also have the additional action of downregulating MMP transcription. As a result of these dual actions, the CMTs may be most beneficial in conditions that are associated with upregulated production of MMPs. Bisphosphonates are compounds that inhibit the mevalonate pathway, and MMP inhibition is an offtarget effect. The mechanism by which these compounds inhibit MMP activity is not well understood. MMPIs have been tested most extensively to date in anticancer clinical trials, where they have exhibited limited effectiveness. The peptidomimetic and nonpeptidomimetic agents are associated with musculoskeletal side effects that prohibit dose escalation, perhaps resulting in sub-optimal dosing to control MMP activity [68]. However, as knowledge of the complexity of MMP action is expanded, it is also recognized that broad spectrum inhibition of MMPs may worsen some disease states, because these drugs would also disrupt the physiological functions of these MMPs in controlling growth and differentiation of cells. Novel approaches that improve the capacity to regulate the activity of specific MMPs may provide better clinical results. One

Mechanical Stimulus Physiological Effects

Growth Factor Receptor

5. Proteolysis – Actions of MMPs

Mechanotransducer 4. Activation

PI3K

Matrix Remodelling

3. Secretion

MAPK

X

X X

Latent MMP

Release of Soluble Factors

ECM

Modification of Cell Adhesion

2. Translation MMP 1. Transcription

Cleavage of Cell Surface Receptors Legend MT-MMP/ TIMP2 complex

Latent MMP

Active MMP

X

Growth Factor

Activating Enzyme

• Endothelial cell proliferation, sprout formation and migration • Arterial Wall Remodelling in response to mechanical stresses • Wound healing

Pathological Effects • Fibrosis • Endothelial cell dysfunction/ apoptosis • Macrophage/Neutrophil infiltration • Disorganized ECM • Smooth muscle cell hyperplasia • Plaque instability

Cell Surface Receptor Drug Discovery Today: Disease Models

Figure 1. MMP production and activation: physiological and pathological consequences. This schematic illustrates regulation of MMP production as well as steps in the peri-cellular activation process. Activation of MMPs will lead to proteolysis of extracellular matrix components, release of matrix bound factors, modification of cell-matrix adhesion, and alterations in the profile of cell surface receptors. These actions contribute to physiological maintenance and remodelling of vascular compartments. However, excessive proteolysis leads to pathological consequences, and escalation of numerous disease states. PI3K – phosphoinositide 3-kinase, MAPK – mitogen activated protein kinases, MMP – matrix metalloproteinase, and ECM – extracellular matrix

www.drugdiscoverytoday.com

9

Drug Discovery Today: Disease Models | Proteolytic degrading processes in the microcirculation

promising area is that of MMP-specific blocking antibodies. Recently, a highly selective blocking antibody targeting MT1-MMP, DX-2400, was reported to reduce endothelial cell migration, tumor metastasis and tumor progression [69]. Another avenue of development is that of exosite inhibitors, which are allosteric inhibitors that interact with non-active site domains on the MMP molecule, facilitating opportunities for identification of novel MMP-specific inhibitors (as reviewed in [70]). Few researchers to date have explored the efficacy of MMPIs to treat cardiovascular pathologies in which MMP activity is upregulated. A recent study provides evidence that chronic administration of a selective MMP inhibitor (XL784) was able to reverse hypertension in Dahl salt-sensitive rats [71], indicating the potential usefulness of MMPIs in combating this disease. The increasing availability of new generation, highly selective MMPIs provides an opportunity to further develop these investigations.

Conclusion Regulation of MMP expression and activity is multi-factorial (summarized in Fig. 1). While numerous control mechanisms of MMPs have been well documented in vitro, further research needs to be conducted to understand the dominant processes underlying the production and activation of these crucial enzymes under specific physiological and pathological conditions. Knowledge of these mechanisms will contribute to more effective manipulation of their activity under pathological conditions.

Acknowledgement TLH received funding from NSERC.

11

12

13

14

15

16 17

18

19 20 21 22 23

24

25 26 27

References 1 Woessner, J.F., Jr (1994) The family of matrix metalloproteinases. Ann. N. Y. Acad. Sci. 732, 11–21 2 Birkedal-Hansen, H. et al. (1993) Matrix metalloproteinases: a review. Crit. Rev. Oral. Biol. Med. 4, 197–250 3 Huovila, A.P. et al. (2005) Shedding light on ADAM metalloproteinases. Trends Biochem. Sci. 30, 413–422 4 Salter, R.C. et al. (2010) ADAMTS proteases: key roles in atherosclerosis? J. Mol. Med. 88, 1203–1211 5 Yan, C. and Boyd, D.D. (2007) Regulation of matrix metalloproteinase gene expression. J. Cell Physiol. 211, 19–26 6 Alfonso-Jaume, M.A. et al. (2006) Cardiac ischemia-reperfusion injury induces matrix metalloproteinase-2 expression through the AP-1 components FosB and JunB. Am. J. Physiol. Heart Circ. Physiol. 291, H1838–H1846 7 Spinale, F.G. (2007) Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 87, 1285–1342 8 Clark, I.M. et al. (2008) The regulation of matrix metalloproteinases and their inhibitors. Int. J. Biochem. Cell Biol. 40, 1362–1378 9 Boyd, P.J. et al. (2005) MAPK signaling regulates endothelial cell assembly into networks and expression of MT1-MMP and MMP-2. Am. J. Physiol. Cell Physiol. 288, C659–C668 10 Haas, T.L. (2005) Endothelial cell regulation of matrix metalloproteinases. Can. J. Physiol. Pharmacol. 83, 1–7

10

www.drugdiscoverytoday.com

28

29

30

31

32

33

34

35

Vol. 8, No. 1 2011

Liu, X. et al. (2010) Role of AP-1 and RE-1 binding sites in matrix metalloproteinase-2 transcriptional regulation in skeletal muscle atrophy. Biochem. Biophys. Res. Commun. 396, 219–223 Han, X. et al. (2003) Transcriptional up-regulation of endothelial cell matrix metalloproteinase-2 in response to extracellular cues involves GATA-2. J. Biol. Chem. 278, 47785–47791 Doyle, J.L. and Haas, T.L. (2009) Differential role of beta-catenin in VEGF and histamine-induced MMP-2 production in microvascular endothelial cells. J. Cell Biochem. 107, 272–283 Takahashi, M. et al. (2002) Identification of membrane-type matrix metalloproteinase-1 as a target of the beta-catenin/Tcf4 complex in human colorectal cancers. Oncogene 21, 5861–5867 Knapinska, A.M. et al. (2005) Molecular mechanisms regulating mRNA stability: physiological and pathological significance. Curr. Genomics 6, 471–486 Kandasamy, A.D. et al. (2010) Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix. Cardiovasc. Res. 85, 413–423 Steele, R. et al. (2010) MBP-1 upregulates miR-29b that represses Mcl-1, collagens, and matrix-metalloproteinase-2 in prostate cancer cells. Genes Cancer 1, 381–387 Roy, S. et al. (2009) MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc. Res. 82, 21–29 Ra, H.J. and Parks, W.C. (2007) Control of matrix metalloproteinase catalytic activity. Matrix Biol. 26, 587–596 Nagase, H. (1997) Activation mechanisms of matrix metalloproteinases. Biol. Chem. 378, 151–160 Murphy, G. et al. (1999) Mechanisms for pro matrix metalloproteinase activation. APMIS 107, 38–44 Strongin, A.Y. et al. (1995) Mechanism of cell surface activation of 72-kDa type IV collagenase. J. Biol. Chem. 270, 5331–5338 Brooks, P.C. et al. (1996) Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alphav beta3. Cell 85, 683–693 Tchougounova, E. et al. (2005) A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J. Biol. Chem. 280, 9291–9296 Sariahmetoglu, M. et al. (2007) Regulation of matrix metalloproteinase-2 (MMP-2) activity by phosphorylation. FASEB J. 21, 2486–2495 Baker, A.H. et al. (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J. Cell Sci. 115, 3719–3727 Noda, M. et al. (2003) RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling. Cancer Metastasis Rev. 22, 167–175 Haas, T.L. et al. (2000) Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle. Am. J. Physiol. Heart Circ. Physiol. 279, H1540–H1547 Rivilis, I. et al. (2002) Differential involvement of MMP-2 and VEGF during muscle stretch- versus shear stress-induced angiogenesis. Am. J. Physiol. Heart Circ. Physiol. 283, H1430–H1438 Rullman, E. et al. (2007) A single bout of exercise activates matrix metalloproteinase in human skeletal muscle. J. Appl. Physiol. 102, 2346–2351 Rullman, E. et al. (2009) Endurance exercise activates matrix metalloproteinases in human skeletal muscle. J. Appl. Physiol. 106, 804–812 Chintala, S.K. et al. (1996) Role of extracellular matrix proteins in regulation of human glioma cell invasion in vitro. Clin. Exp. Metastasis 14, 358–366 Haas, T.L. et al. (1998) Three dimensional type I collagen lattices induce coordinate expression of matrix metalloproteinases MT1-MMP and MMP2 in microvascular endothelial cells. J. Biol. Chem. 273, 3604–3610 Chan, V.T. et al. (1998) Membrane type matrix metalloproteinases in human dermal microvascular endothelial cells: expression and morphogenetic correlation. J. Invest. Derm. 111, 1153–1159 Milkiewicz, M. et al. (2007) Static strain stimulates expression of matrix metalloproteinase-2 and VEGF in microvascular endothelium via JNKand ERK-dependent pathways. J. Cell Biochem. 100, 750–761

Vol. 8, No. 1 2011

36

37

38 39

40

41 42

43

44

45

46

47

48

49

50 51

52

Drug Discovery Today: Disease Models | Proteolytic degrading processes in the microcirculation

Ispanovic, E. and Haas, T.L. (2006) JNK and PI3K differentially regulate MMP-2 and MT1-MMP mRNA and protein in response to actin cytoskeleton reorganization in endothelial cells. Am. J. Physiol. Cell Physiol. 291, C579–C588 Ispanovic, E. et al. (2008) Cdc42 and RhoA have opposing roles in regulating membrane type 1-matrix metalloproteinase localization and matrix metalloproteinase-2 activation. Am. J. Physiol. Cell Physiol. 295, C600–C610 Nateri, A.S. et al. (2005) Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437, 281–285 Ha, C.H. et al. (2008) VEGF stimulates HDAC7 phosphorylation and cytoplasmic accumulation modulating matrix metalloproteinase expression and angiogenesis. Arterioscler. Thromb. Vasc. Biol. 28, 1782–1788 Xu, J. et al. (2001) Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J. Cell Biol. 154, 1069–1079 Bergers, G. et al. (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 Onimaru, M. et al. (2010) An autocrine linkage between matrix metalloproteinase-14 and Tie-2 via ectodomain shedding modulates angiopoietin-1-dependent function in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 30, 818–826 Dean, R.A. et al. (2007) Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis. Mol. Cell Biol. 27, 8454–8465 Haas, T.L. et al. (2007) Involvement of MMPs in the outward remodeling of collateral mesenteric arteries. Am. J. Physiol. Heart Circ. Physiol. 293, H2429–H2437 Ruddy, J.M. et al. (2010) Differential effect of wall tension on matrix metalloproteinase promoter activation in the thoracic aorta. J. Surg. Res. 160, 333–339 Raffetto, J.D. and Khalil, R.A. (2008) Matrix metalloproteinases in venous tissue remodeling and varicose vein formation. Curr Vasc Pharmacol 6, 158–172 Yun, S. et al. (2002) Transcription Factor Sp1 phosphorylation induced by shear stress inhibits membrane type 1-matrix metalloprotinase expression in endothelium. J. Biol. Chem. 277, 34808–34814 Milkiewicz, M. et al. (2008) Shear stress-induced Ets-1 modulates protease inhibitor expression in microvascular endothelial cells. J. Cell Physiol. 217, 502–510 Newby, A.C. (2008) Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler. Thromb. Vasc. Biol. 28, 2108–2114 Lemarie, C.A. et al. (2010) Extracellular matrix alterations in hypertensive vascular remodeling. J. Mol. Cell Cardiol. 48, 433–439 Kuzuya, M. et al. (2003) Deficiency of gelatinase a suppresses smooth muscle cell invasion and development of experimental intimal hyperplasia. Circulation 108, 1375–1381 Kuzuya, M. et al. (2006) Effect of MMP-2 deficiency on atherosclerotic lesion formation in apoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 26, 1120–1125

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67 68 69

70

71

Galis, Z.S. et al. (2002) Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ. Res. 91, 852–859 Chen, K.C. et al. (2011) OxLDL up-regulates microRNA-29b, leading to epigenetic modifications of MMP-2/MMP-9 genes: a novel mechanism for cardiovascular diseases. FASEB J. Castro, M.M. et al. (2011) Matrix metalloproteinases: Targets for doxycycline to prevent the vascular alterations of hypertension. Pharmacol. Res. Shiraya, S. et al. (2006) Hypertension accelerated experimental abdominal aortic aneurysm through upregulation of nuclear factor kappaB and Ets. Hypertension 48, 628–636 Castro, M.M. et al. (2008) Metalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. Atherosclerosis 198, 320–331 Rodrigues, S.F. et al. (2010) Matrix metalloproteinases cleave the beta2adrenergic receptor in spontaneously hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 299, H25–H35 Tran, E.D. et al. (2010) Enhanced matrix metalloproteinase activity in the spontaneously hypertensive rat: VEGFR-2 cleavage, endothelial apoptosis, and capillary rarefaction. J. Vasc. Res. 47, 423–431 Raffetto, J.D. and Khalil, R.A. (2008) Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem. Pharmacol. 75, 346–359 Myers, J.E. et al. (2005) MMP-2 levels are elevated in the plasma of women who subsequently develop preeclampsia. Hypertens. Pregnancy 24, 103–115 Matsusaka, H. et al. (2006) Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension 47, 711–717 Spinale, F.G. et al. (2010) Cardiac restricted overexpression of membrane type-1 matrix metalloproteinase causes adverse myocardial remodeling following myocardial infarction. J. Biol. Chem. 285, 30316–30327 Lee, J.G. et al. (2005) Intronic regulation of matrix metalloproteinase-2 revealed by in vivo transcriptional analysis in ischemia. Proc. Natl. Acad. Sci. U. S. A. 102, 16345–16350 Lindsey, M.L. et al. (2006) Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 290, H232–H239 Ducharme, A. et al. (2000) Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J. Clin. Invest. 106, 55–62 Konstantinopoulos, P.A. et al. (2008) Matrix metalloproteinase inhibitors as anticancer agents. Int. J. Biochem. Cell Biol. 40, 1156–1168 Gialeli, C. et al. (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 278, 16–27 Devy, L. et al. (2009) Selective inhibition of matrix metalloproteinase-14 blocks tumor growth, invasion, and angiogenesis. Cancer Res. 69, 1517–1526 Sela-Passwell, N. et al. (2010) Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition? Biochim. Biophys. Acta 1803, 29–38 Williams, J.M. et al. (2011) Evaluation of metalloprotease inhibitors on hypertension and diabetic nephropathy. Am. J. Physiol. Renal Physiol. 300, F983–F998

www.drugdiscoverytoday.com

11