Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Matrix Metalloproteinase-2

  • Brandon Y. H. Chan
  • Andrej Roczkowsky
  • Ramses Ilarraza
  • Richard Schulz
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101708


Historical Background

Matrix metalloproteinase-2 (MMP-2), previously named 72 kDa type IV collagenase or gelatinase A, belongs to the MMP family of calcium and zinc-dependent endopeptidases. MMPs were originally considered to be secreted proteases which play a major role in degrading extracellular matrix (ECM) proteins. In addition to its canonical role in ECM remodelling, MMP-2 has many nonmatrix extracellular and intracellular substrates (Schulz 2007; Spinale 2007). The list of identified MMP-2 substrates continues to grow and includes sarcomeric proteins, membrane receptors, cytokines, and growth factors. Consequently, MMP-2 regulates a vast range of physiological processes, from angiogenesis to wound healing and tissue remodeling. However, aberrant activation of MMP-2 contributes to many pathophysiological conditions, including inflammation, cancer metastasis, and cardiovascular diseases, making it a target of interest for therapeutic inhibition.

The field of MMP biology was introduced in 1962 when Gross and Lapiere reported a collagenolytic activity secreted from tadpoles undergoing metamorphosis (Gross and Lapiere 1962). This activity was later attributed to the enzyme collagenase (MMP-1), the first identified member of the MMP family. Nearly two decades later, another MMP (MMP-2) was identified from an invasive mouse tumor, which was capable of degrading basement membrane type IV collagen (Liotta et al. 1979). In 1988, the primary amino acid sequence of MMP-2 was determined and the protein was identified as a 72 kDa secreted zymogen (Collier et al. 1988). This enzyme, which was then named “gelatinase A” and finally MMP-2, was purified from human rheumatoid synovial fibroblasts. This provided an important leap in our understanding of MMP-2, revealing its optimum pH, inhibition profile, and some of its preferred substrates (Okada et al. 1990). MMP-2 was found to degrade numerous ECM proteins in vitro, including gelatin (denatured collagen), laminin, fibronectin, and type IV and V collagens (Okada et al. 1990).

Initially, only extracellular proteins were studied as potential MMP-2 substrates, as MMPs were believed to be secreted and activated exclusively in the extracellular compartment. This idea was later challenged by two important observations: first, MMP-2 was unequivocally localized inside heart muscle cells, particularly in association with the sarcomere (Wang et al. 2002); and, second, MMPs including MMP-2 could be directly activated by a critical endogenous mediator of cellular oxidative stress, peroxynitrite, without requiring the proteolytic removal of its inhibitory prodomain (Okamoto et al. 2001; Viappiani et al. 2009). Subsequently, the first intracellular target of MMP-2, troponin I, was identified (Wang et al. 2002), opening the doors to a new realm of intracellular MMP-2 biology. Intracellular MMP biology has led to the identification of numerous intracellular MMP-2 targets, beyond troponin I, relevant to heart disease and other pathologies, including α-actinin, titin, myosin light chain-1, glycogen synthase kinase-3β, and dystrophin (a growing list), to name a few.

Biosynthesis and Structure

In humans, the MMP-2 gene (also known as CLG4) contains 13 exons and spans 27.9 kb of the q12.2 region in chromosome 16. MMP-2 is ubiquitous across all tissues and was previously thought to be a constitutively expressed protein. However, it has become evident that MMP-2 gene expression is tightly regulated and can be upregulated in response to endothelin-1, interleukin 1β, angiotensin II, tumor necrosis factor-α, estrogen, progesterone, and hypoxia (Galis et al. 1995; Bergman et al. 2003). Various relevant transcription factors have been found to bind to elements in the MMP-2 gene promoter, amongst them, AP-1, AP-2, PU1, YB-1, p53, Stat3, NF-kB, SP-1, and silencing proteins. In cardiac myocytes, hypoxia stimulates MMP-2 gene expression through binding of Fra1-JunB and FosB-JunB heterodimers to the distal AP-1 site in the MMP-2 promoter (Bergman et al. 2003; Lovett et al. 2012). Absence of a TATA box in the MMP-2 promoter contributes to the existence of several transcriptional start locations. Recent in silico analysis has revealed the high probability of an alternative promoter within the first intron of the MMP-2 gene, shown to express an N-terminally truncated isoform of MMP-2 missing the first 76 amino acids (MMP-2NTT-76), under conditions of oxidative stress (Lovett et al. 2012). A splice variant of MMP-2 (MMP-2NTT-50) which results in the truncation of the first 50 amino acids has also been identified (Ali et al. 2012).

Human MMP-2 is translated as an inactive 72 kDa zymogen consisting of five structural domains: an N-terminal predomain containing a secretory signal peptide (aa 1–29), an autoinhibitory prodomain (aa 30–109), a catalytic zinc domain accommodating three fibronectin type II repeats (aa 110–435), a hinge region, and a hemopexin domain (aa 466–660, Fig. 1). The N-terminal secretory signal peptide of MMP-2 is inefficient in targeting nascent MMP-2 to the endoplasmic reticulum, resulting in approximately half of MMP-2 remaining in the cytosol (Ali et al. 2012). Additionally, the two intracellular N-terminally truncated isoforms of MMP-2, MMP-2NTT-76 and MMP-2NTT-50, lack the N-terminal signal peptide and part of the prodomain (Ali et al. 2012; Lovett et al. 2012). The catalytic domain of MMPs contains a conserved zinc binding motif HEXXHXXGXXH, with three histidines coordinating the catalytic Zn2+. The conserved Cys102 residue in the prodomain determines MMP-2’s enzymatic capacity by interacting with the catalytic Zn2+. Three fibronectin type II repeats in the catalytic domain of MMP-2 aid in its binding to gelatin. Additional substrate specificity is conferred by the hemopexin domain, which is linked to the catalytic domain via the hinge region. The hemopexin domain is critical for the proteolytic activation of MMP-2 (see below).
Matrix Metalloproteinase-2, Fig. 1

MMP-2 domain structures. MMP-2 contains an inefficient signal sequence (or predomain) in its first 29 amino acids, such that almost half of MMP-2 remains inside the cell. Cys102 in the autoinhibitory prodomain binds the catalytic zinc atom, to render it in its latent form. MMP-2 can be activated by peroxynitrite dependent S-glutathiolation of Cys102. Two further intracellular MMP-2 isoforms, MMP-2NTT-50 and MMP-2NTT-76, have recently been discovered. MMP-2NTT-50 is a splice variant present under basal conditions. MMP-2NTT-76 expression is induced under conditions of oxidative stress and is thought to be proteolytically active. Extracellular form of MMP-2 (MMP-2EC) is formed following the proteolytic removal of its prodomain in the extracellular space. *Denotes possible activation by peroxynitrite as per S-glutathiolated MMP-2

Activation and Regulation

Proteolytic Activation of Extracellular MMP-2

The proteolytic activation of 72 kDa MMP-2 zymogen to an active 64 kDa protease has been well studied. Approximately half of nascent MMP-2 that is synthesized enters into the endoplasmic reticulum, where the signal peptide is removed and the protease is packaged in vesicles at the Golgi complex to be secreted at the cell membrane. MMP-2 is then activated in the pericellular or extracellular space via the so-called cysteine-switch mechanism (Van Wart and Birkedal-Hansen 1990). Once synthesized, the critical Cys102 residue in the MMP-2 propeptide domain forms a thiol-Zn2+ bond with the catalytic Zn2+, keeping it in an inactive, zymogen form. The 72 kDa MMP-2 zymogen is then docked at the membrane, forming a ternary complex with tissue inhibitor of metalloproteinase-2 (TIMP-2) and membrane-type 1 MMP (MT1-MMP). TIMP-2 anchors the 72 kDa MMP-2 zymogen at the membrane by forming a noncovalent complex at the hemopexin domain. MT1-MMP hydrolyses Asn56-Leu57 of the MMP-2 zymogen, removing part of the propeptide domain to form a partially active MMP-2 intermediate. Partial propeptide processing disrupts the Cys102-Zn2+ interaction, exposing the catalytic Zn2+ to H2O. Subsequently, already formed 64 kDa MMP-2 cleaves the reminder of the propeptide by hydrolyzing the Asn109-Tyr110 peptide bond, yielding a catalytically active, extracellular 64 kDa MMP-2.

Nonproteolytic Activation of Intracellular MMP-2

Recent evidence reveals that there are at least three moieties of intracellular MMP-2, including 72 kDa S-glutathiolated MMP-2, MMP-2NTT-50, and MMP-2NTT-76 (Ali et al. 2012; Lovett et al. 2012) (Fig. 1). The intracellular 72 kDa MMP-2 zymogen can be directly activated by posttranslational modification, without the proteolytic removal of the propeptide domain, during oxidative stress (Schulz 2007). The Cys102-Zn2+ bond can be disrupted by a posttranslational modification in the presence of peroxynitrite and cellular glutathione. This reaction triggers the S-glutathiolation of the Cys102 residue in the highly conserved PRCGVPD motif found in the propeptide domain. S-glutathiolation of Cys102 in MMP-2 changes the conformation of the enzyme to expose the catalytic Zn2+, forming active, 72 kDa S-glutathiolated MMP-2 (Viappiani et al. 2009). Note that S-glutathiolation adds only 303 Da to its molecular weight, insufficient for resolution from its precursor form in SDS-polyacrylamide gel electrophoresis. MMP-2NTT-76 lacks most of the inhibitory propeptide domain and, therefore, is active upon expression. It is unknown if MMP-2NTT-50 is active or requires covalent modification of its prodomain for activity.

Posttranslational Regulation of MMP-2

MMP-2 is modulated by natural endogenous inhibitors, TIMP-1, TIMP-2, TIMP-3, and TIMP-4, which inhibit MMP-2 and other MMPs by binding to them in a 1:1 stoichiometric ratio. Although the inhibitory profile of each TIMP on specific members of the MMP family has not been fully determined yet, TIMP-2 shows some selectivity for MMP-2. As described above, TIMP-2 has a dual role on MMP-2 activity by facilitating both its proteolytic activation and inhibition.

MMP-2 is the first MMP whose activity was shown to be modulated via reversible phosphorylation (Sariahmetoglu et al. 2007). Cellular MMP-2 likely has several different phosphorylated forms. Its activity is markedly enhanced upon dephosphorylation with alkaline phosphatase. Although the endogenous kinases (and phosphatases) regulating its phosphorylation are yet unknown, protein kinase C is able to phosphorylate MMP-2 in vitro (Sariahmetoglu et al. 2007) and protein phosphatase 2a is likely involved in its dephosphorylation (Sariahmetoglu et al. 2012). Protein kinase C-mediated phosphorylation significantly inhibits MMP-2 activity, in a reversible manner. Some protein kinase C phosphorylated residues identified in MMP-2 include Ser32, Ser160, Ser365, Thr250, and Tyr271, all of which are highly conserved amongst MMPs. Several of these phosphorylation sites are located within the collagen binding domain and catalytic cleft, directly involved in substrate binding and turnover. The role of the phosphorylation status of MMP-2 in its activation by peroxynitrite has been reported (Jacob-Ferreira et al. 2013).

Subcellular Localization of MMP-2

Given that MMP-2 possesses a signal sequence, its function was initially believed to be limited to the extracellular space. Despite this, approximately half of the newly synthesized MMP-2 is not secreted and remains cytosolic because the signal sequence present in MMP-2 is inefficient. Further complexity arises from the identification of two intracellular, N-terminal truncated MMP-2 isoforms that lack the entire signal sequence and at least one of which is active upon its expression (Ali et al. 2012; Lovett et al. 2012). The biological relevance of the truncated isoforms is not fully understood. In the last 15 years, MMP-2 has been localized to many specific subcellular structures, including the sarcomere, cytoskeleton, nucleus, caveolae, mitochondria, and the mitochondria-associated membrane, a specialized region of the endoplasmic reticulum (Hughes et al. 2014) (Fig. 2). These diverse intracellular localizations clearly suggest that MMP-2 isoforms have differential biological roles in both cellular physiology and disease.
Matrix Metalloproteinase-2, Fig. 2

Intracellular targets of MMP-2. MMP-2 is localized to several subcellular locals including the caveolae, cytoskeleton, sarcomere, sarco/endoplasmic reticulum, nucleus, mitochondria, and mitochondria-associated membrane. Confirmed intracellular MMP-2 substrates are identified below the subcellular organelle title where they are located. Putative targets are denoted with a question mark

Substrates of MMP-2

Extracellular Matrix Substrates

The extracellular matrix (ECM) provides the physical scaffold for cells to maintain tissue architecture. The ECM also regulates cell signaling by binding a plethora of cytokines and growth factors and creating microenvironments. MMPs degrade membrane-bound proteins which in turn influence cellular growth, proliferation, and migration (Fig. 3). Collagen is the most abundant fibrous protein component of the extracellular matrix. Although not classified as a collagenase, MMP-2 can degrade type IV, V, VII, and X collagen. As suggested by its original name of gelatinase A, MMP-2 cleaves gelatin (denatured collagen). Glycoproteins such as fibronectin and laminin, which form the basement membrane of cells, have also been added to the large list of ECM MMP-2 targets (Giannelli et al. 1997; Kenny et al. 2008).
Matrix Metalloproteinase-2, Fig. 3

Extracellular targets of MMP-2. MMP-2EC degrades protein components of the extracellular matrix, including collagen (type IV, V, VII, and X), gelatin (denatured collagen), fibronectin, and laminin. Degradation of the ECM releases bound growth factors (TGF-1β and VEGF) and cytokines (IL-1β). MMP-2 also targets non-ECM proteins in the extracellular space, including β-dystroglycan, pro-IL-1β, and pro-TGF-β1. The actions of extracellular MMP-2 contribute to cell invasion, angiogenesis, fibroblast proliferation, and chemotaxis

Extracellular Nonmatrix Substrates

Understanding of the full gamut of MMP-2 substrates has been hampered by the term “matrix” in its own name. MMP-2 functions extend far beyond the extracellular matrix barriers that limit cell movement and link cells together. MMP-2 cleaves the chemokine stromal cell-derived factor-1α (SDF-1α), producing a neurotoxic fragment SDF-1(5–67) (Rodriguez et al. 2010). The chemokine monocyte chemoattractant protein-3 (MCP-3) is cleaved and inactivated by MMP-2. Cleaved MCP-3 dampens inflammatory processes by binding to CC-chemokine receptors (Rodriguez et al. 2010). MMP-2 can regulate intercellular structure and tensile strength by cleaving transmembrane proteins such as β-dystroglycan (Court et al. 2011) (Fig. 2). β-Dystroglycan provides structural support to cells by linking the cytoskeleton to the extracellular matrix. Under physiological and pathological conditions, β-dystroglycan is tightly regulated, in part, by MMP-2 mediated proteolytic turnover. MMP-2 also has emerging roles in mobilizing growth factors and cell signaling by proteolytic release of nonmatrix extracellular proteins. MMP-2 has been shown to cleave vascular endothelial growth factor from its inhibitory complex, which consists of connective tissue growth factor and heparin affin regulatory peptide (Dean et al. 2007). MMP-2 has also been shown to activate latent transforming growth factor-β and inactivate interleukin-1β (Ito et al. 1996; Yu and Stamenkovic 2000).

Intracellular Substrates


In 2002, the use of immunogold electron microscopy revealed that MMP-2 has a distinct sarcomeric staining pattern, and it was found localized to the thin myofilaments of cardiac myocytes. Using confocal microscopy and biochemical techniques, MMP-2 was found to colocalize with the thin filament regulatory protein, troponin I. Purified troponin I was tested for its susceptibility to be cleaved by MMP-2 in vitro, and it was rapidly proteolyzed in a concentration-dependent manner within 20 min of incubation at 37°C. In hearts subjected to oxidative stress injury by ischemia-reperfusion injury, increased MMP-2 activity was associated with cleavage of troponin I, an effect which was prevented with MMP inhibitors. This marked the first evidence of the intracellular localization of MMP-2, which greatly expanded our understanding of its biological effects beyond the extracellular matrix. Since then, the list of MMP-2 targets in the sarcomere has grown to include myosin light chain-1, α-actinin, and titin, all of which are essential for efficient contractile function (Hughes and Schulz 2014).


MMP-2 also targets the cytoskeletal proteins α-actinin and dystrophin (Schulz 2007; Buchholz et al. 2014). Isolated rat hearts infused with peroxynitrite showed reduced levels of myocardial α-actinin and impaired contractile function as a result of increased MMP-2 activity (Sung et al. 2007). Dystrophin is a key linker protein that connects the extracellular matrix through the cell membrane via dystroglycans, to the sarcolemma. During cardiac ischemia, increased MMP-2 activity resulted in dystrophin proteolysis (Buchholz et al. 2014), an effect that was prevented by ischemic preconditioning, a treatment which attenuates oxidative stress-induced MMP-2 activity (Lalu et al. 2002). It is also important to mention that desmin, another intermediate filament protein, is susceptible to proteolysis by MMP-2 in vitro (Sung et al. 2007). Whether this takes place in vivo remains an open question.


The caveolae are small invaginations in the cell membrane which regulate endocytosis and signal transduction by trafficking macromolecules and signaling proteins. The caveolae are stabilized by caveolins. The MMP-2 amino acid sequence encodes seven consensus binding motifs for caveolin-1 scaffolding domains, four in the collagen binding domain, and three in the hemopexin domain (Chow et al. 2007). It is postulated that MMP-2 activity is inhibited when bound to caveolins due to steric interference of substrate binding.


The nucleus consists of a proteinaceous matrix that resembles the extracellular matrix and supports various nuclear processes. Interestingly, the C-terminus of the MMP-2 sequence encodes a nuclear localization sequence (Kwan et al. 2004). In the nucleus, MMPs have been hypothesized to cleave transcription factors, proteins involved in DNA repair, such as poly-ADP-ribose polymerase, and to regulate mitotic events in the nucleus (Kwan et al. 2004). Nuclear MMP-2 is thought to have a protective role by preventing excessive poly-ADP-ribose polymerase activity, which could exhaust energy stores in the cell.


Recent findings suggested that MMP-2 may be localized to the mitochondria (Lovett et al. 2012). However, their mitochondrial preparations should contain a portion of the endoplasmic reticulum (ER) which is bound to the mitochondria, known as the mitochondria-associated membrane. Because MMP-2 localizes to the ER, the MMP-2 that was detected in the mitochondria may have originated from the ER. Further investigation determined that while most of mitochondrial MMP-2 was found in the MAM, a small but significant proportion does reside in mitochondria (Hughes et al. 2014). Lovett’s group suggest that the MMP-2NTT-76 isoform is mitochondrial and only expressed in cells following oxidative stress injury. Calreticulin, a mitochondria-associated membrane-resident Ca2+ regulatory protein, can be cleaved by MMP-2 in vitro, suggesting MMP-2 in the mitochondria-associated membrane may have an indirect role on mitochondrial function (Hughes et al. 2014).

Role in Disease

MMP-2 plays an active role in several physiological and developmental processes, including wound healing, inflammation, bone resorption, angiogenesis, and embryogenesis (Visse and Nagase 2003). In this chapter, we will focus on the pathophysiological role of MMP-2 in cancer and heart disease.

MMP-2 in Cancer Metastasis

A 72 kDa type IV collagenase secreted by a metastatic murine tumor was first described in 1979 and later identified as MMP-2 (Liotta et al. 1979). Highly aggressive cancers, including carcinomas and sarcomas, exhibit elevated levels of MMP-2 activity. Given the role of ECM-localized MMP-2 on cellular proliferation, adhesion, and motility, MMP-2 has been implicated in tumor invasion and cancer metastasis. Upregulation of MMP-2 in tumor cells facilitates cancer metastasis by cleaving the ECM proteins laminin and fibronectin (Giannelli et al. 1997; Kenny et al. 2008).

The role of MMP-2 in cancer metastasis is more dynamic than degradation of the ECM between adjacent cells alone. The ECM provides a physical barrier between epithelial tissues from the surrounding mesenchyme. MMP-2 actively facilitates epithelial-mesenchymal transition in cancer metastasis by degrading the ECM to allow tumor cell migration (Radisky and Radisky 2010). To supply metastatic tumors with the essential nutrients, tumors drive angiogenesis by releasing soluble growth factors, such as TGF-β and VEGF, from the ECM, and inhibitory complexes (Yu and Stamenkovic 2000; Dean et al. 2007). Most cancer cells increase latent TGF-β production to trigger the epithelial-mesenchymal transition and enhance angiogenesis around the tumor microenvironment. MMP-2 then activates TGF-β by cleaving it in its latent state.

MMP-2 in Cardiovascular Diseases

MMP-2 is ubiquitously expressed in all cell types in the heart. Triggered by ischemia or inflammatory processes, MMP-2 cleavage of ECM and intracellular proteins leads to reduced contractile function and pathological intra- and extracellular matrix remodeling and, ultimately, cardiovascular disease (Schulz 2007; Spinale 2007). The severity of heart failure is associated with the level of MMP-2 in the heart. MMP-2 activation occurs rapidly in reversible ischemia-reperfusion injury (Wang et al. 2002) and also following more severe ischemia causing myocardial infarct (Spinale 2002). Following infarct, MMP-2 induces remodeling of the left ventricle, causing it to become enlarged and dilated, losing its ability to contract. The MMP inhibitor doxycycline attenuates myocardial infarct related injury (Villarreal et al. 2003) and was shown in a clinical trial to reduce detrimental ventricular remodeling following myocardial infarction (Cerisano et al. 2014). MMP-2 is also involved in atherosclerosis, specifically during the late phase of plaque rupture. Plaque rupture is a consequence of extensive degradation of ECM proteins collagen and elastin. In the vasculature, angiotensin II-induced hypertension upregulates MMP-2, but not MMP-9 expression, contributing to increased arterial wall thickness and reduced lumen diameter via excess collagen and elastin turnover. Excessive proteolysis of these ECM proteins triggers maladaptive regeneration of a hypertrophic arterial wall, resulting in hypertension (Spinale 2002).

MMP-2 Inhibitors

Prior to the identification of all the MMPs known to date, many broad spectrum MMP inhibitors were developed to treat chronic inflammatory disorders and cancers. Despite their efficacy, the therapeutic utility of these drugs were hindered by undesirable side effects, likely from inhibiting essential MMPs such as MMP-1. Over time, our understanding of the role of each MMP has significantly improved. Since only certain MMPs should be targeted to treat various diseases, including cancer and heart disease, developing more specific inhibitors, even those which specifically target intracellular isoforms of MMP-2, may address the shortcomings of previously developed MMP inhibitors.


Since its discovery as a type IV collagenase over 35 years ago, the field of MMP-2 biology has grown exponentially. Numerous non-ECM protein substrates for MMP-2 have been identified, both inside and outside the cell. Intracellular MMP-2 activity arises from peroxynitrite dependent activation of the MMP-2 zymogen and the injury-induced expression of MMP-2NTT-76. Intracellular MMP-2 contributes to cellular injury by proteolyzing specific proteins in several specific subcellular compartments, impairing cellular function. In the extracellular and pericellular space, MMP-2 is activated via proteolytic removal of its prodomain, resulting in the degradation of ECM proteins, membrane receptors, and cytokines. MMP-2 activity is tightly regulated at both the gene and protein level to control proteolysis of MMP-2 substrates. Dysregulation of MMP-2 activity contributes to a variety pathological conditions, including cancer, inflammation, and cardiovascular diseases. Discovery of new MMP-2 substrates and specific inhibitors will likely provide insight into novel roles for MMP-2 in health and disease.



We thank Dawne Colwell for her help with graphics. Research in the Schulz lab is supported by the Canadian Institutes of Health Research (FDN 143299) and the Heart and Stroke Foundation of Canada. Brandon Chan received a WCHRI graduate studentship award which is funded by the support of the Stollery Children’s Hospital Foundation through the Women and Children’s Health Research Institute.


  1. Ali MA, Chow AK, Kandasamy AD, Fan X, West LJ, Crawford BD, et al. Mechanisms of cytosolic targeting of matrix metalloproteinase-2. J Cell Physiol. 2012;227:3397–404. doi: 10.1002/jcp.24040.PubMedCrossRefGoogle Scholar
  2. Bergman MR, Cheng S, Honbo N, Piacentini L, Karliner JS, Lovett DH. A functional activating protein 1 (AP-1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and JunB-FosB heterodimers. Biochem J. 2003;369:485–96. doi: 10.1042/BJ20020707.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Buchholz B, Perez V, Siachoque N, Miksztowicz V, Berg G, Rodríguez M, et al. Dystrophin proteolysis: a potential target for MMP-2 and its prevention by ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2014;307:H88–96. doi: 10.1152/ajpheart.00242.2013.-Dystrophin.PubMedCrossRefGoogle Scholar
  4. Cerisano G, Buonamici P, Valenti R, Sciagrà R, Raspanti S, Santini A, et al. Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: the TIPTOP trial. Eur Heart J. 2014;35:184–91. doi: 10.1093/eurheartj/eht420.PubMedCrossRefGoogle Scholar
  5. Chow AK, Cena J, El-Yazbi AF, Crawford BD, Holt A, Cho WJ, et al. Caveolin-1 inhibits matrix metalloproteinase-2 activity in the heart. J Mol Cell Cardiol. 2007;42:896–901. doi: 10.1016/j.yjmcc.2007.01.008.PubMedCrossRefGoogle Scholar
  6. Collier IE, Wilhelm SM, Eisen AZ, Marmer BL, Grant GA, Seltzer JL, et al. H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J Biol Chem. 1988;263:6579–87.PubMedGoogle Scholar
  7. Court FA, Zambroni D, Pavoni E, Colombelli C, Baragli C, Figlia G, et al. MMP2-9 cleavage of dystroglycan alters the size and molecular composition of Schwann cell domains. J Neurosci. 2011;31:12208–17. doi: 10.1523/JNEUROSCI.0141-11.2011.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Dean RA, Butler GS, Hamma-Kourbali Y, Delbe J, Brigstock DR, Courty J, et al. 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. 2007;27:8454–65. doi: 10.1128/MCB.00821-07.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Libby P. Enhanced expression of vascular matrix metalloproteinases induced in vitro by cytokines and in regions of human atherosclerotic lesions. Ann NY Acad Sci. 1995;748:501–7.PubMedCrossRefGoogle Scholar
  10. Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science. 1997;277:225–8.PubMedCrossRefGoogle Scholar
  11. Gross J, Lapiere CM. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA. 1962;48:1014–22.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Hughes BG, Fan X, Cho WJ, Schulz R. MMP-2 is localized to the mitochondria-associated membrane of the heart. Am J Physiol Heart Circ Physiol. 2014;306:H764–H70. doi: 10.1152/ajpheart.00909.2013.-Matrix.PubMedCrossRefGoogle Scholar
  13. Hughes BG, Schulz R. Targeting MMP-2 to treat ischemic heart injury. Basic Res Cardiol. 2014;109:424. doi: 10.1007/s00395-014-0424-y.PubMedCrossRefGoogle Scholar
  14. Ito A, Mukaiyama A, Itoh Y, Nagase H, Thogersen IB, Enghild JJ, et al. Degradation of interleukin 1beta by matrix metalloproteinases. J Biol Chem. 1996;271:14657–60.PubMedCrossRefGoogle Scholar
  15. Jacob-Ferreira AL, Kondo MY, Baral PK, James MN, Holt A, Fan X, et al. Phosphorylation status of 72 kDa MMP-2 determines its structure and activity in response to peroxynitrite. PLoS One. 2013;8:e71794. doi: 10.1371/journal.pone.0071794.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Kenny HA, Kaur S, Coussens LM, Lengyel E. The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. J Clin Invest. 2008;118:1367–79. doi: 10.1172/JCI33775.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Kwan JA, Schulze CJ, Wang W, Leon H, Sariahmetoglu M, Sung M, et al. Matrix metalloproteinase-2 (MMP-2) is present in the nucleus of cardiac myocytes and is capable of cleaving poly (ADP-ribose) polymerase (PARP) in vitro. FASEB J. 2004;18:690–2.PubMedCrossRefGoogle Scholar
  18. Lalu MM, Csonka C, Giricz Z, Csont T, Schulz R, Ferdinandy P. Preconditioning decreases ischemia/reperfusion-induced release and activation of matrix metalloproteinase-2. Biochem Biophys Res Commun. 2002;296:937–41.PubMedCrossRefGoogle Scholar
  19. Liotta LA, Abe S, Robey PG, Martin GR. Preferential digestion of basement membrane collagen by an enzyme derived from a metastatic murine tumor. Proc Natl Acad Sci USA. 1979;76:2268–72.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Lovett DH, Mahimkar R, Raffai RL, Cape L, Maklashina E, Cecchini G, et al. A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity. PLoS One. 2012;7:e34177. doi: 10.1371/journal.pone.0034177.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Okada Y, Morodomi T, Enghild JJ, Suzuki K, Yasui A, Nakanishi I, et al. Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties. Eur J Biochem. 1990;194:721–30.PubMedCrossRefGoogle Scholar
  22. Okamoto T, Akaike T, Sawa T, Miyamoto Y, van der Vliet A, Maeda H. Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem. 2001;276:29596–602. doi: 10.1074/jbc.M102417200.PubMedCrossRefGoogle Scholar
  23. Radisky ES, Radisky DC. Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J Mammary Gland Biol Neoplasia. 2010;15:201–12. doi: 10.1007/s10911-010-9177-x.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Rodriguez D, Morrison CJ, Overall CM. Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics. Biochim Biophys Acta. 2010;1803:39–54. doi: 10.1016/j.bbamcr.2009.09.015.PubMedCrossRefGoogle Scholar
  25. Sariahmetoglu M, Crawford BD, Leon H, Sawicka J, Li L, Ballermann BJ, et al. Regulation of matrix metalloproteinase-2 (MMP-2) activity by phosphorylation. FASEB J. 2007;21:2486–95. doi: 10.1096/fj.06-7938com.PubMedCrossRefGoogle Scholar
  26. Sariahmetoglu M, Skrzypiec-Spring M, Youssef N, Jacob-Ferreira AL, Sawicka J, Holmes C, et al. Phosphorylation status of matrix metalloproteinase 2 in myocardial ischaemia-reperfusion injury. Heart. 2012;98:656–62. doi: 10.1136/heartjnl-2011-301250.PubMedCrossRefGoogle Scholar
  27. Schulz R. Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches. Annu Rev Pharmacol Toxicol. 2007;47:211–42. doi: 10.1146/annurev.pharmtox.47.120505.105230.PubMedCrossRefGoogle Scholar
  28. Spinale F. Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res. 2002;90:520–30. doi: 10.1161/01.res.0000013290.12884.a3.PubMedCrossRefGoogle Scholar
  29. Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev. 2007;87:1285–342. doi: 10.1152/physrev.00012.2007.PubMedCrossRefGoogle Scholar
  30. Sung MM, Schulz CG, Wang W, Sawicki G, Bautista-Lopez NL, Schulz R. Matrix metalloproteinase-2 degrades the cytoskeletal protein alpha-actinin in peroxynitrite mediated myocardial injury. J Mol Cell Cardiol. 2007;43:429–36. doi: 10.1016/j.yjmcc.2007.07.055.PubMedCrossRefGoogle Scholar
  31. Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA. 1990;87:5578–82.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Viappiani S, Nicolescu AC, Holt A, Sawicki G, Crawford BD, Leon H, et al. Activation and modulation of 72 kDa matrix metalloproteinase-2 by peroxynitrite and glutathione. Biochem Pharmacol. 2009;77:826–34. doi: 10.1016/j.bcp.2008.11.004.PubMedCrossRefGoogle Scholar
  33. Villarreal FJ, Griffin M, Omens J, Dillmann W, Nguyen J, Covell J. Early short-term treatment with doxycycline modulates postinfarction left ventricular remodeling. Circulation. 2003;108:1487–92. doi: 10.1161/01.CIR.0000089090.05757.34.PubMedCrossRefGoogle Scholar
  34. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39. doi: 10.1161/01.RES.0000070112.80711.3D.PubMedCrossRefGoogle Scholar
  35. Wang W, Schulze CJ, Suarez-Pinzon W, Dyck J, Sawicki S, Schulz R. Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury. Circulation. 2002;106:1543–9. doi: 10.1161/01.cir.0000028818.33488.7b.PubMedCrossRefGoogle Scholar
  36. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14:163–76.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Brandon Y. H. Chan
    • 1
    • 2
  • Andrej Roczkowsky
    • 1
    • 2
  • Ramses Ilarraza
    • 1
    • 2
  • Richard Schulz
    • 1
    • 2
  1. 1.Departments of Pediatrics and PharmacologyMazankowski Alberta Heart Institute, Cardiovascular Research Centre, University of AlbertaEdmontonCanada
  2. 2.462 Heritage Medical Research CentreUniversity of AlbertaEdmontonCanada