Matrix metalloproteinases are involved in cardiovascular diseases.

Basic & Clinical Pharmacology & Toxicology, 2014, 115, 301–314

Doi: 10.1111/bcpt.12282

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Matrix Metalloproteinases are Involved in Cardiovascular Diseases Aline Azevedo1, Alejandro F. Prado1, Raquel C. Antonio1, Joao P. Issa2 and Raquel F. Gerlach1,2 1

Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil and 2Department of Morphology and Physiology, Faculty of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil (Received 15 June 2013; Accepted 26 June 2014) Abstract: This MiniReview describes the essential biochemical and molecular aspects of matrix metalloproteinases (MMPs) and briefly discusses how they engage in different diseases, with particular emphasis on cardiovascular diseases. There is compelling scientific evidence that many MMPs, especially MMP-2, play important roles in the development of cardiovascular diseases; inhibition of these enzymes is beneficial to many cardiovascular conditions, sometimes precluding or postponing end-organ damage and fatal outcomes. Conducting comprehensive discussions and further studies on how MMPs participate in cardiovascular diseases is important, because inhibition of these enzymes may be an alternative or an adjuvant for current cardiovascular disease therapy.

General Aspects of MMPs Matrix metalloproteinases also called matrixins consist of endopeptidases that participate in extracellular matrix (ECM) degradation; they represent the main group of proteases implicated in this biological process. MMPs play essential physiological roles in the organism, including embryonic development, morphogenesis, angiogenesis, ovulation, cervical dilation, bone tissue remodelling, wound healing and apoptosis [1,2]. MMPs also act in cardiovascular remodelling and have a distinct spatial and temporal role that ensures normal physiology of the heart [3] and vasculature [4]. Genetic alterations in these enzymes and MMP expression are related to the pathological processes of arthritis, fibrosis, tumour growth and metastasis, nephritis, neurological and periodontal diseases, hypertension and atherosclerosis [2]. To date, scientists have identified 24 MMP genes in human beings, most of which consist of multidomain proteins [1]. It is possible to regulate the MMP activities at different levels; gene expression regulation, zymogens activation and active enzymes inhibition by specific inhibitors underlie this regulation [5]. Members of the Matrix Metalloproteinase Family In 1962, Gross and Lapiere reported the activity of an MMP for the first time: it was the collagenolytic activity verified in tadpole tissues undergoing metamorphosis [6]. In 1975, Woolley et al. [7] purified the first human collagenase from

Author for correspondence: Racquel F. Gerlach, FORP/USP, Avenida do Cafe, S/N, 14040-904 Ribeir~ao Preto, SP, Brazil (fax +55 16 36024102, e-mail [email protected]).

rheumatoid synovium; this enzyme exhibited properties similar to those of the tadpole collagenase. Currently, MMPs comprise a family of 26 enzymes that occur in human tissues as well as organisms such as the fruit fly (Drosophila melanogaster) [8], a nematode (Caenorhabditis elegans) [9], sea urchin (Paracentrotus lividus) [10], hydra (Hydra vulgaris) [11] and plants (Arabidopsis thaliana) [12]. Matrix metalloproteinases -4, -5 and -6 do not exist, since they had been proposed, and shortly later identified as one of the MMPs that had already been described. MMP classification depends on their substrate specificity, primary structure and location in the cell; they are categorized as collagenases, gelatinases, stromelysins, matrilysins and membrane-type (MT) MMPs. Three collagenases have been identified so far: collagenase 1 (MMP-1), collagenase 2 (MMP-8) and collagenase 3 (MMP13). Gelatinases A (MMP-2) and B (MMP-9) constitute the group of gelatinases. MMP-3, MMP-10 and MMP-11 correspond to stromelysins 1, 2 and 3, respectively. MMP-7 and MMP-26 belong to the group of matrilysins, the smallest MMPs. Two types of MT-MMPs exist – four type I transmembrane proteins (MMP-14, MMP-15, MMP-16 and MMP-24) and two glycosylphosphatidylinositol (GPI)-anchored proteins (MMP-17 and MMP-25). MMP-12, MMP-19, MMP-20, MMP21, MMP-23, MMP-27 and MMP-28 have not been catalogued in any of the subgroups mentioned above. Structure and Function Matrix metalloproteinases are synthesized as zymogens; they can be secreted or membrane-bound. Subsequent MMP processing and activation allow for controlled substrate degradation.

© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)

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MMPs consist of multidomain zinc metalloproteinases; they share a common domain structure composed of a signal peptide, a propeptide, a catalytic domain, a hinge region and, in the majority of the cases, a C-terminal domain [2]. The propeptide domain (about 80 amino acids) contains a conserved cysteine residue, which interacts with the zinc ion in the catalytic site and maintains the protein in its inactive state. To activate MMPs, it is necessary to open this so-called cysteine ‘switch’ [13]. The MMP catalytic domain (about 170 amino acids long) displays a zinc-binding motif HEXGHXXGXXH characteristic of the metzincin superfamily of proteinases, followed by an invariant methionine involved in a structural feature called ‘Met-turn’ [14]. Mechanism of Activation To activate MMPs, it is necessary to dissociate the interaction between the cysteine residue of the propeptide domain and the zinc ion of the catalytic domain [13]. Many agents can activate MMPs, including detergents (sodium dodecyl Sulphate, for instance), chaotropic agents, chemicals like HOCl (hypochlorous acid) and mercurial compounds and enzymes (trypsin and plasmin). Physical agents can also open up the MMP structure and expose the zinc ion. Substances that react with sulfhydryl groups (NEM – N-ethylmaleimide, GSSG – oxidized glutathione, HOCl, APMA – amino-phenyl mercuric acetate) will act in two steps. Firstly, they will interact with the cysteine of the MMP propeptide, which will result in MMP autolysis and activation. Proteolytic enzymes (trypsin, plasmin) can cleave this propetide, without affecting its cysteine residue. In a second step, the activated molecules will catalyse their autolysis, permanently removing the MMP propeptide and activating the MMP [15]. Since the beginning of the research into MMPs, many studies have taken advantage of the fact that different agents and proteinases activate MMPs. For example, gelatin zymography, which identifies gelatinase activity in gels, has been used for decades; it evidences the activity of different MMP forms (containing the catalytic domain) after SDS is washed off. Because enzyme exposure to SDS denatures the protein and dissociates the interaction between the propeptide and the catalytic domain, the zymograms reveal MMP forms that bear the propeptide domain and exhibit catalytic activity. The MMP molecules renature upon SDS removal, but the propeptide no longer interacts with the catalytic domain. Thus, even ‘inactive’ (MMPs containing the propeptide) enzymes appear on the zymograms. The common mechanism that activates latent MMP forms in tissues probably involves a cascade of proteolysis that includes other proteinases, such as other MMPs, as well as proteinases belonging to other classes. Cell-associated plasmin generation by urokinase-like plasminogen activator engages in one of the mechanisms that activate MMPs [16]. Active cell surface MTI-MMP (MMP-14) also activates MMPs. It cleaves MMP-2, potentiating further self-cleavage reactions. MMP-14 may also activate MMP-13 directly. A more likely event is that MMP-2 activates MMP-13, and then, MMP-2, MMP-3

and MMP-13 activate MMP-9. MMP-3 can also activate MMP-13. The generation of partially active or totally active MMPs allows a cascade of cleavages that generate fully active enzymes [17,18]. Matrix metalloproteinase-2 activation involves the formation of a complex of MMP-2/tissue inhibitor of metalloproteinase 2 (TIMP-2) and MMP-14 on the cell surface. For MMP-14 to catalyse proMMP-2 activation, proMMP-2 has to exist as a complex with TIMP-2, in which the MMP inhibitor binds to the proMMP-2 hemopexin domain [19–22]. In the currently accepted model of MMP-2 activation, two MMP-14 molecules join in the activator complex. The proteolytic site of one of the MMP-14 molecules binds to TIMP-2, functioning as a bridge that poises proMMP-2 for activation by a neighbouring MMP-14 molecule not yet inactivated by TIMP-2 [23]. This MMP-14/TIMP-2 complex acts as a receptor, to bind proMMP-2 to the cell surface through interaction of the exposed TIMP-2 C-terminal domain with the proMMP-2 PEX domain. MMP-14 forms a homophilic complex on the cell surface via the PEX domain, which facilitates proMMP-2 activation [24]. Autolytic cleavage by MMP-2 completes the activation, to give a lower molecular form of 64 kDa, without the propeptide domain [25]. The proteolytic removal of the propeptide region disturbs the interaction of cysteine with zinc in the propeptide and exposes the catalytic domain. It has been shown that peroxynitrite (ONOO-) activates proMMP-2 without removing the propeptide, to maintain the same molecular weight of inactive MMP-2 (72 kDa). It was also proposed that ONOO and cellular glutathione (GSH) react with the cysteine residue in the conserved domain; Sglutathiolation takes place, disrupting the thiolate bond with the catalytic Zn2+ ion and furnishing an active 72-kDa (fulllength) MMP-2 [26]. Glutathiolation also activates MMP-1, MMP-8 and MMP-9 [27]. Other Structural Considerations A flexible proline-rich hinge region follows the catalytic domain in all the MMP family members, except for MMP-7 (matrilysin-1), MMP-23 (CA-MMP) and MMP-26 (matrilysin2). Thereafter (towards the C-terminal end), most MMPs present another large domain known as the hemopexin-binding domain (about 210 amino acids), which probably operates during substrate recognition and MMP activity control. This is the case of collagenases MMP-1, MMP-8, MMP-13 and MMP-18, where the hemopexin domain is required for the triple helical interstitial collagen cleavage [28]. The hemopexin domain is also important for interactions between two MMP14 molecules during the pro-MMP-2 cell surface activation [24]. The gelatinases MMP-2 and MMP-9 have an insert of three fibronectin type II repeats in the catalytic domain. This insert generates a collagen-binding domain that binds and degrades type IV collagen or denatured collagens (gelatins) [29,30], which accounts for the high affinity of these MMPs for gelatin. This feature underlies the MMP-2 and MMP-9 purification process – an affinity column that contains gelatin bound to


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MATRIX METALLOPROTEINASES ARE INVOLVED IN CARDIOVASCULAR DISEASES

sepharose beads is the first choice to obtain pure MMP-2 and MMP-9. Recently, our group has successfully expressed and purified the full-length human recombinant of MMP-2 from bacteria, to achieve a highly soluble and functional protein for in vitro and in vivo studies [31]. Individual MMPs vary; for example, MT-MMPs either have a transmembrane domain and cytoplasmic tail at the C-terminus (MMP-14, MMP-15, MMP-16 and MMP -24) or anchor to GPI (MMP-17 and MMP-25). They have a furin recognition sequence RX[R/K]R at the propeptide C-terminus, so they undergo intracellular activation and probably express active enzymes on the cell surface [1]. Regulation of MMP Expression and Activity Gene transcription, post-translational control and interaction with endogenous inhibitors (TIMPs) regulate MMP expression and activity at different levels. At the transcriptional level, a number of MMP promoters contain cis-elements, allowing a set of trans-activators including AP-1, PEA3, Sp-1, b-catenin/ Tcf-4 and NF-kB to regulate MMP gene expression. The MMP-2/MMP-9 (gelatinases) or MMP-1/MMP-8 (collagenases) promoters have distinct compositions. The majority contains a TATA box and an AP-1-binding site as well as an upstream PEA3-binding site that is often adjacent to the AP-1binding site [32]. The MMP-8, -11 and -21 promoters also contain a TATA box, but they lack a proximal AP-1 site. On the other hand, promoters of other MMPs, including MMP-2, -14 and -28, do not harbour a TATA box. Hence, MMP transcription from them starts at multiple sites and relies mainly on the ubiquitous Sp-1 family of transcription factors, which bind to a proximal GC box. Studies have demonstrated that a functional AP-1 site mediates MMP-2 transcription in cardiac cells through binding of distinctive Fra1-JunB and FosB-JunB heterodimers [33]. This report was the first to state that defined members of the Fos and Jun transcription factor families specifically regulate this gene under conditions relevant to critical pathophysiological processes. Alfonso-Jaume et al. [34] showed that induction (via oxidant stress) of discrete AP1 transcription factor components enhances MMP-2 transcription and translation following ischaemia/reperfusion injury. As for the post-translational control, phosphorylation may modify MMP-2 activity. Indeed, human recombinant MMP-2 can undergo in vitro phosphorylation in the presence of protein kinase C (PKC), with changes in five different residues [35]. The TIMPs can also inhibit MMPs in a 1:1 stoichiometric ratio. Four types of TIMPs exist: TIMP-1, -2, -3 and -4. TIMPs are involved in cardiac fibrosis, angiogenesis and apoptosis [36]. Cardiac enriched TIMP-4 plays an important role in matrix remodeling in myocardial infarct (MI), because it may inhibit MMP-9 activity [37]. An MMP/TIMP imbalance participates in structural and functional changes in hypertensive heart disease [38]. Matrix metalloproteinases do not exist in the extracellular space only. MMP-3 occurs in the cell nucleus. Authors have also proposed that MMP activity in the nucleus of tumour

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cells might lead to cell death [39]. MMP-2 exists in mitochondria and the endoplasmatic reticulum [40], as well as in the nucleus [41] and in the sarcomeres of cardiomyocytes [42– 45]. Little information exists about the nuclear localization sequence in MMPs or about the biological mechanism that regulates MMP entry and activation in the nucleus. One report has shown that MMP-2 present in the nucleus of cardiac myocytes engages in protein degradation during DNA repair of poly (ADP-ribose) involved in apoptosis [41]. MMP and Cardiovascular Diseases Cardiovascular diseases are the leading causes of morbidity and mortality worldwide (http://www.who.int/mediacentre/factsheets/fs317/en/index.html/March 2013). MI and sudden death due to chronic diseases such as vascular atherosclerosis, heart failure, tissue remodeling and inflammation take central roles in these pathological processes. Matrix metalloproteinase activation alters the architecture of the plaque and may directly help to disrupt plaques [46–49]. Higher MMP activity underlies aneurysms progression [50,51] and plaque rupture in coronary artery disease [52–54]. MMPs and aneurysm. Aneurysm consists in destruction and functional loss of elastin in the aortic medium. MMP plays a significant role in weakening the ECM components (elastin, collagen, fibronectin and proteoglycans), thus harming the aortic wall. MMP-1 [55], MMP-2 [55,56], MMP-3 [55], MMP-8 [57] and MMP-9 [51,56] levels are elevated in aneurysm. TIMP-3 knockout reduces collagen and elastin and raises proteolytic activities, to generate aneurysm 4 weeks after angiotensin II infusion [58]. On the other hand, TIMP-2 knockout attenuates aneurysm progression, because it plays a part in MMP-2 activation [59]. Animals transgenic for MMP-2 display increased mid-ventricular coronary luminal areas coupled with foci of aneurysmal dilation, ectasia and perivascular fibrosis [60]. MMP-12 knockout mice present attenuated aneurysm growth [61]. MMP-9 or MMP-12 protects apolipoprotein E-deficient (Apo E / ) mice against atherosclerotic plaque destruction and ectasia [62]. MMPs and diabetes. In addition, MMPs are involved in other cardiovascular diseases like diabetes. Diabetic patients exhibit impaired glucose metabolism, and the ensuing hyperglycaemia results in many complications, including vasculature damage and inability to heal wounds. In these patients, vascular damage culminates in ischaemia, which in turn contributes to the persistence of wounds. In other words, vascular damage leads to inflammation and triggers reactive oxygen species (ROS) production, which harms the ECM and prevents wound closure [63,64]. Analysis of MMP-2 and MMP-9 expression in the left ventricle (LV) of the heart of diabetic animals revealed MMP-2 down-regulation and significant MMP-9 up-regulation [65].


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MMPs and myocardial infarct. Studies accomplished on the remodeling process following MI have detected higher MMP-1, MMP-2, MMP-3 and MMP-9 expression and activity in human, rat and porcine hearts [66– 70]. Up-regulated MMP activity after infarction suggests that MMPs participate in the cardiac repair process, so these enzymes might play some roles in infarction healing, including early ECM degradation, cell migration (inflammatory cells, fibroblasts), angiogenesis, remodelling of newly synthesized connective tissue and regulation of growth factor activities [2,8]. As discussed by Spinale et al. [3], MMPs assume roles in both the healing process after myocardial injury [71–78] and the adverse remodelling that follows MI [37,79–89]. In the early period after MI (first 72 hr), a wound healing response occurs with appropriate cytokines amplification, inflammatory cells influx and fibroblasts proliferation/transdifferentiation to a myofibroblast phenotype [90–94]. Inflammatory cells and myofibroblasts release some MMPs that can facilitate proteolysis of ECM components, to form nascent wound. Studies performed with transgenic constructs support a relationship between MMP induction and activation after MI [72,73]. Transgenic deletion of MMP-9, MMP-2 or MMP-7 in murine constructs of MI alters the post-MI remodelling process in particular ways [71,74–76]. Molecular imaging approaches in murine models have provided a temporal map of MMP induction and activation within LV during the remodelling process [77,88]. MMP-2 and MMP-9 promoter activation increases within the MI and border zones soon after MI, but higher MMP-2 promoter activation also occurs within the viable remote region in addition to the atrium [77,88]. These studies have cast light on the MMP types that may cause LV remodelling as well as on the regional and temporal aspects of post-MI MMP induction. Data suggest that certain MMP types, such as MMP-1, may not contribute to the adverse LV remodeling process post-MI [88,95]. Studies have demonstrated that global MMP inhibition is unnecessary and that targeting a potential subset of MMP types may be effective [96]. Past studies have suggested that pharmacological MMP inhibition soon after MI is not mandatory; indeed, it can be commenced after the initial wound healing period is complete (first 72 hr) [3]. Studies using MMP inhibitors and genetically modified mice have evidenced the MMP function during LV healing and remodeling following MI. Rohde et al. [84] showed that in vivo MMP inhibition attenuates early LV dilation 4 days after experimental MI in mice. Matrix metalloproteinase inhibitors can be classified as specific or non-specific. Non-specific inhibitors like batimastat, marimastat, GM-6001 (ilomastat or gelardin), PD-166793 and ONO-4817 act by chelating the Zn2+ ion and have found application in many models of the disease [97]. Moreover, the peptides containing the HWGF motif, CRRHWGFEFC and CTTHWGFTLC are selective MMP-9 and MMP-2 inhibitors, respectively [98,99], but their clinical use is uncertain because they are susceptible to proteolysis inside the body. Chemically modified tetracyclines (CMTs) also inhibit MMP activity [100]. CMT-3 suppresses MMP-2 and -9 activities

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along with collagenase activity, to improve pathological cardiovascular remodeling. In fact, CMT-3 has been administered to human beings in clinical trials [101]. A common tetracycline antibiotic, doxycycline, has been used as MMP inhibitor in heart failure patients. It inhibits several MMPs and improves ischaemia/reperfusion injury at the onset of MI. Pre-treatment with sub-antimicrobial dose doxycycline (SDD) 2 days prior to MI reduces cardiac dilation and enhances endothelial function in rats [102]. Periostat (a commercial name for doxycycline formulated for periodontal disease) is the only MMP inhibitor that has received approval for clinical use [103]. Brown et al. [104] reported that administration of SDD (two doses of 20 mg/day) to patients with coronary artery disease for months decreased C-reactive protein (CRP) by 46% in the group that received SDD (p = 0.007), but not in the placebo group. Meanwhile, interleukin-6 (IL-6) concentrations went down in the SDD group, but not in the placebo group. Additionally, MMP-9 activity diminished by 50% in the SDD group, suggesting that SDD exerts beneficial effects on inflammation, to probably promote plaque stability [104].

MMPs and atherosclerosis. In atherosclerosis, the MMPs play a part in vascular smooth muscle cell migration and neointima formation after localized vascular injury [105–107]. Active MMPs present in the atherosclerotic lesions may contribute to plaque destabilization by degrading ECM components [108]. Atherosclerotic human vessels display increased MMP-2, MMP-3 and MMP-9 levels as compared with healthy human vessels [80,109]. Studies using knockout mice have suggested that MMP-2, MMP-8, MMP-9 and MMP-12 are implicated in plaque development and burden. MMP-8 [110] and MMP-2 [111] knockout mice with ApoE / atherosclerosis develop significantly reduced atherosclerosis as compared with ApoE / mice. After temporary carotid artery ligation, MMP-9 deficiency also leads to significantly diminished intimal hyperplasia in ApoE / mice [112]. Studies on MMP-12 showed that this MMP promotes lesion initiation and progression in rabbits [113] and that MMP-12 knockout mice with Apo / background have smaller lesions in the brachiocephalic artery without altered lesion growth in aorta [62]. In contrast, genetic MMP-11 [106] or MMP-7 [114] deletion in ApoE / mice does not modify the vascular phenotype or the atherosclerotic lesion, respectively. Additionally, MMP-11 deletion in ApoE / knockout mice enhances neointimal formation after vascular injury as compared with wildtype mice [106]. Matrix metalloproteinases assume a complex role in angiogenesis regulation. In atherosclerosis, angiogenesis occurs by neovascularization that starts in vasa vasorum of the adventicia and then extends towards the intima layer [115,116]. This process may be a response to tissue hypoxia, in an attempt to decrease ischaemia in the tissue of the atherosclerotic lesion. Still concerning atherosclerosis, angiogenesis is also associated with increased atherosclerotic lesion and higher atherosclerotic


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plaque instability [117,118]. Indeed, treatment of ApoE / mice with angiostatin (inhibitor of angiogenesis) retards lesion progression [119]. Unstable plaques exist within vasa vasorum and apoptotic macrophages, suggesting that these microvessels play essential roles in atherosclerotic lesion progression and instability [120,121]. Matrix metalloproteinase-14 regulates endothelial cell migration and lumen formation within the ECM by controlling capillary sprouting, collagenolysis and endothelial cell invasion [122,123]. MMP-7 is an important regulator in angiogenesis, because it promotes endothelial proliferation [124]. On the other hand, MMP-9 takes on both a pro- and an antiangiogenic role [125,126]. Fang et al. [127] reported fewer endothelial cells or plaque angiogenesis in the atherosclerotic plaques of MMP-8 knockout mice, indicating that MMP-8 is important in ECM angiogenesis in vitro, ex vivo and in vivo. In recent years, countless researchers have investigated how MMP-2 functions in the vascular system. An in vivo study has described stable and significant remodelling of small mesenteric arteries with increased MMP-2 activity after 7 and 15 days of hypertension induced by L-NAME (a non-specific inhibitor of oxide nitric synthase). After 28 days, the MMP-2 activity drops to baseline levels [128]. In this same work, the authors concluded that the eutrophic remodelling of small arteries is associated with varying expression of several proteins involved in cell–matrix interactions.

MMPs and hypertension. Matrix metalloproteinases play an essential role in hypertension [129]. Our group has reported elevated MMP-2 levels in the thoracic aortas [130–138] and heart [139,140] of two-kid-

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ney, one-clip (2K1C) hypertensive rats. A time course study testing MMP-2 involvement in the vascular alterations in the aorta tissue of 2K1C rats revealed structural changes, augmented MMP-2 levels, gelatinolytic activity, oxidative stress and endothelial dysfuncition in the early phase (2 weeks) of hypertension [134], suggesting that treatment with doxycycline [130,135] and tempol [131] after the first 2 weeks still reverts the alterations in 2K1C rats. Other drugs like dihydropyridines [136], spironolactone and hydrochlorothiazide [133] also prevent vascular remodelling and diminish the MMP-2 levels and gelatinolytic activity in the aortas of 2K1C rats. Many papers have suggested that drugs used in the therapy of cardiovascular diseases may affect MMP activity. However, recent investigations have shown that the MMP inhibitory effect of antihypertensive drugs is more likely a consequence of reduced oxidative stress and lower blood pressure rather than a result of direct MMP inhibition by these drugs. This is the situation verified for the calcium channel blockers nifedipine (0, 1, 10 and 100 mM) and metoprolol (0, 1, 10 and 100 mM) [141] as well as for the diuretics hydrochlorothiazide (0, 1, 10 and 100 lM) and spironolactone (SPRL) (0, 1, 10 and 100 lM) [133]. Figure 1 schematically illustrates those effects. As for treatment of hypertensive patients with enalapril, it significantly lowers systolic and diastolic blood pressure after four and 8 weeks and does not affect MMP activity in the plasma [142]. A series of studies [143–146] claimed that captopril and lisinopril exhibit inhibitory activity. An in vitro study by Reinhardt et al. [145] described the inhibitory activity of captopril, lisinopril and ramiprilate at millimolar concentrations on the basis of zymograms. Since then, zymogram-based other studies have continued to find gelatinases (MMP-2 and MMP-9) inhibition at millimolar concentrations

Fig. 1. Biochemical and functional modifications that occur in aorta and heart of 2K1C animals treated or not with drugs. Heart and aorta of 2K1C-hypertensive animals show increased oxidative stress, and increased matrix metalloproteinase-2 (MMP-2) activity and protein expression. This is associated with cardiac remodelling and endothelial and cardiac dysfunction. Increased oxidative stress also leads directly to cardiac and endothelial dysfunction. The treatment with non-selective inhibitors of MMPs (doxycycline – doxy), reactive oxygen species scavenger (Tempol) and antihypertensive drugs (AHD: spironolactone, hydrochlorothiazide, nifedipine and metoprolol) decreased oxidative stress, activity and expression of MMP-2, reverted the cardiac and vascular remodelling and improved endothelial and cardiac function. Doxy also decreased MMP-2 activity. *AHD: antihypertensive drugs were only tested in thoracic aorta isolated from 2K1C animals.


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only. Indeed, as suggested by Reinhardt et al. [145], the drug has difficulty entering the gel matrix. Most importantly, in the clinical setting, these drugs do not emerge at millimolar levels in the plasma or tissues. Using highly purified MMP-2 to conduct both zymograms and fluorimetric assays, Kuntze et al. [147] have shown that the pH of the solution containing the drugs may drop, which is most likely the reason why a series of studies in the past found that captopril inhibited gelatinases. MMP-2 inhibition by captopril and lisinopril only takes place at millimolar levels. Thus, direct MMP inhibition by ACE inhibitors is probably only a minor concern for the in vivo situation [147]. On the other hand, many other studies have shown that in vitro incubation with captopril and lisinopril significantly reduces MMP-2 activity and that in vivo treatment with these drugs fails to identify a reduction in the accessible pool of MMP-2 protein [146]. Moreover, it has been demonstrated that captopril and lisinopril at 20–40 and 200–400 mM, respectively, lower the gelatinolytic activity in a dose-dependent manner [144]. Chronic exposure to lead, a toxic metal, is associated with hypertension in animals [148–150] and human beings [151– 153]. Rats that were exposed to lead and treated with doxycycline for 8 weeks showed attenuated MMP-2 expression (mRNA, protein and activity) and reduced systolic blood pressure. In addition, the treatment with doxycycline also prevented lead-induced increases in the MMP-2/TIMP-2 mRNA ratio. These results suggested that MMP-2 could play a role in lead-induced increases in blood pressure [154]. Studies have also found increased MMP-2 activity in the thoracic aorta of diabetic rats [155,156]; treatment with doxycycline reverts the endothelial dysfunction in these animals [156,157]. Hence, increased MMP-2 activity may account for the lower vascular relaxation induced by acetylcholine. Zeydanli et al. [157] showed that MMP-2 activity and expression do not change in diabetic rats, but doxycycline decreases lipid peroxidation and cellular glutathione level measured in the plasma and improves endothelial dysfunction. Treatment of animals with doxycycline diminishes the oxidative stress, which may account for improved vascular relaxation [130,135,155–158]. Castro et al. [158] described that treatment of 2K1C rats with doxycycline decreases oxidative stress while increasing nitric oxide (NO) bioavailability in endothelial cells; it also improves endothelium-dependent vascular relaxation induced by A23187 [158]. Another study reported that treatment of spontaneously hypertensive rats (SHRs) with doxycycline reduces oxidative stress and blood pressure [159]. ROS and NO interaction can decrease NO bioavailability and generate peroxynitrite; ROS may also affect the bioavailability of the cofactors of NO synthase, leading to uncoupled NOS, which in turn starts to produce O2 rather than NO [160–164]. Spontaneously hypertensive rats have elevated proteolytic activity in the heart, aorta [159] and plasma [165–168]. Tran et al. [168] showed that SHRs aged between 12 and 18 weeks present increased MMP-2, MMP-9 and MMP-7 activity in the plasma. In a study that evaluated the MMP-2 and MMP-9 lev-

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els in the plasma of 8-week-old SHRs and untreated hypertensive patients (with no other diseases) and compared them with data obtained for control animals and normotensive patients, the authors concluded that hypertensive patients and SHR display higher MMP-9 levels as compared with normotensive patients and control animals. These parallel alterations in clinical hypertension and in SHR suggest an important role for MMPs in hypertension [167]. Matrix metalloproteinases cleave the beta-2 adrenergic receptor, which appears to be a potentially important mechanistic link between higher MMP expression and activity and increased arteriolar tone in SHR [169]. Treatment with acid ammonium pyrrolidine dithiocarbamate (DPTC) blocks this process, suggesting that NFkB is responsible for increased MMP activity and cleavage of the beta-2 adrenergic receptor [170]. However, which MMP is involved in this process remains unclear. Matrix metalloproteinase-9 knockout mice present increased vasodilation (endothelium-dependent) of resistance arteries and elevated endothelial nitric oxide synthase (eNOS) [171]. In fact, vasoconstriction of arterioles and venules rapidly takes place in the microvessels of Wistar rats after injection of MMP-7 and MMP-9 (alone or in association) [169]. The mechanism involved in vasoconstriction by MMP-7 depends on the epidermal growth receptor (EGHF), which is important to maintain the vascular tone [172]. In vitro studies have indicated that MMP-2 could play an important role in blood pressure regulation by cleaving big endothelin-1 (Big ET-1) to a potent vasoconstrictor, endothelin-1 (ET 1–32) [173]. In vitro MMP-2 could also cleave the vasodilator peptide CGRP (calcitonin gene-related peptide), generating degradation products with lower vasodilating action [174]. Also, in vitro MMP-2 could act on adrenomedullin, producing metabolites with lower vasodilating potential and which actually act as vasoconstrictors [175]. Playing the role of a coadjuvant, MMP-2 released by thrombin action could cleave Big ET-1, to give 1–32 ET. In arteries with endothelium, 1–32 ET forms NO and prostaglandin 2 (PGI2), which culminates in vascular relaxation; in endothelium-denuded arteries, vasoconstriction should occur [176].

MMPs and cardiomyopathies. A few studies have shown that MMP-2 alone accounts for severe morphological changes and functional loss in the heart. Matsusaka et al. [177] reported that the absence of MMP-2 protects the heart from injury-induced increase in the ventricular afterload. A time course study in 2K1C rats showed increased ROS levels, TGF beta expression and MMP-2 activity and expression 15–75 days after arterial clipping. Left ventricular and septum wall thickening and cardiomyocyte hypertrophy were also detected in this situation [178]. Treatment of 2K1C animals with tempol [139] and doxycycline [140] reversed cardiac alterations. Increased MMP-2 in the heart of the transgenic model augments the infarction areas and diminishes the contractile


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function in the hearts of animals subjected to ischaemia/reperfusion [179]. These transgenic mice express active MMP-2 (muted) driven by the myosin heavy chain promoter. The prodomain-muted MMP-2 couples to a c-myc epitope tag, to differentiate the endogenous MMP-2 [180]. Active MMP-2 expression in the heart of transgenic mice results in cardiac functional loss and morphological alterations, marked ventricular remodeling with myocyte hypertrophy, myofilaments lysis, sarcomeres destruction and cardiac fibroblasts proliferation [180]. Increased MMP-2 in the heart also degenerates the heart valves after 12–24 weeks of life [181]. More recently, Lovett et al. [40] verified that oxidative stress in cardiac myocytes induces a novel intracellular (mitochondrial) MMP-2 isoform [40]. This form has an N-terminal truncation (the first methionine corresponds to methionine 77 of the full-length MMP-2) and is shorter (65 kDa). Because this isoform loses part of the propeptide, it probably becomes active at the moment it is translated, so this shorter intracellular MMP-2 form may contribute to the structural and functional cardiac damage that occurs in many cardiovascular diseases leading to heart failure. Moreover, MMP-2 found in sarcomers cleaves many structural cardiac proteins, like troponin I [45], myosin light chain 1 [43], a-actinin [44] and titin [42] contributing to decreased cardiac function. Figure 2 schematically illustrates the activity of MMP-2 on heart proteins and function. Dahi et al. [60] verified that lesions emerge in the coronary arteries during the late period (when higher MMP-2 levels

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exist in the vessels and begin to decrease in cardiomyocytes), which attests to the critical role of increased MMP-2 expression. These authors described that the elastin of arteries loses integrity, fibrous tissue deposits in the adventitia and inflammatory infiltrate increases. The kidney is essential for blood pressure control; after the first week of life, MMP-2 expression by transgenesis (mice) in the epithelial cells of proximal tubules leads to severe structural disorganization of the kidney parenchyma, culminating in changes in the tubular basement membrane, epithelial-mesenchymal transition, tubular atrophy, tubular fibrosis and renal function loss [182]. When it is active in specific organs that are essential for cardiovascular function (heart and kidney), MMP-2 alone is sufficient to induce changes in animals that mimic well-known clinical conditions. This information is very important when one considers (1) studies that have demonstrated the role increased MMP-2 expression plays in the heart and vessels during various cardiac diseases and (2) investigations showing that decreased MMP-2 activity reverses cardiovascular conditions such as hypertension. Understanding how one protease alone (MMP-2) acts in some cardiovascular diseases opens new therapeutic possibilities. Indeed, Periostat has been clinically used in the United States to treat periodontitis, a disease of the gums and teeth [103]. MMPs and periodontitis. Periodontitis is a chronic disease that is highly associated with cardiovascular diseases [183]; this association is important to

Fig. 2. Active matrix metalloproteinase-2 (MMP-2) involvement in cardiac dysfunction in cardiovascular diseases. Inflammatory cells, reactive oxygen species and fibroblast proliferation lead to higher activity and/or increased protein expression of MMP-2 in pathological conditions, including ischaemia/reperfusion, ventricular afterload, 2K1C hypertension and myocardial infarct. The higher level/activity of MMP-2 leads to cardiac dysfunctions (as indicated in the figure) by several ways, including alteration of cardiac cells phenotype (cardiomyocyte hypertrophy) and cardiac remodelling (ventricular dilatation) or degradation of contractile and structural proteins (troponin I, myosin light chain 1, a-actinin and titin) and heart valve degeneration.



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clinically manage cardiovascular conditions [184]. MMPs have already been recognized to be essential to the progress of periodontitis; they are the most important class of proteases to degrade the collagen fibres that constitute the periodontal ligament and maintain the tooth attached to the bone. MMPs are also crucial to the inflammatory response that recruits inflammatory cells to the inflammation site. The FDA has approved doxycycline to treat periodontal disease. This antibiotics reduces some inflammatory markers that are important for cardiovascular events such as cell adhesion molecules (ICAM and VCAM), cytokines, tumour necrosis factor alpha (TNF), CD 40, IL-6, fibrinogen, serum amyloid A (SAA), CRP and lipoprotein phospholipase A2 in the plasma [185]. Treating periodontal disease decreases IL-6 and CRP plasma levels [186,187], reduces the carotid intima diameter the after 6 weeks [188] and diminishes the MMP-8 and MMP-9 plasma concentrations [186]. Moreover, periodontitis has been linked to atherosclerotic development in mice models [105,189,190]. Treatment with doxycycline reduced pro-inflammatory cytokines and MMP-9 plasma levels and diminished atherosclerosis in apoE+/ inoculated with periodontal pathogenic bacteria [191]. Interestingly, MMP-9 has been described as a possible biomarker of cardiovascular events [49,107,192–197]. Therefore, increased MMP activity in the plasma and in organs (and not only an increased pro-inflammatory state) may be the link between periodontitis and cardiovascular diseases. Conclusions Advances have been made towards understanding of the biochemical and structural aspects of MMPs, including their activation and catalytic mechanisms, substrates specificity and mechanism of inhibition. MMPs are involved in many diseases. Using different models, researchers have gathered substantial evidence that MMPs mediate the progress of various cardiovascular diseases. MMP-2 is one of the MMPs that has been extensively described in the heart and in normal and diseased vessels. Our group has shown increased MMP-2 levels in hypertrophic 2K1C aortas of hypertensive rats; administration of a non-specific MMP inhibitor, doxycycline, significantly reduces the blood pressure and completely reverses the structural changes in the vessels. A link between cardiovascular diseases and periodontitis also exists; it may be mediated by MMPs, as both conditions involve increased MMP expression. Further studies on the involvement of specific MMPs in disease models may help elucidate the roles of MMP and aid discovery of new drug targets to treat cardiovascular diseases. Acknowledgements This work was supported by CAPES (Brasilia, Brazil) and FAPESP (State of Sao Paulo Research Foundation, SP, Brazil). A. Azevedo received a fellowship from CAPES (Grant Number 02764/09-1). References 1 Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69:562–73.

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Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases.

Regulation and involvement of matrix metalloproteinases in vascular diseases.

Human pleural effusions are rich in matrix metalloproteinases.

Matrix metalloproteinases in pneumonia.

The matrix-degrading metalloproteinases.

Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in the hair cycle.

Molecular Wound Assessments: Matrix Metalloproteinases.

Matrix metalloproteinases in exercise and obesity.

Matrix Metalloproteinases in Non-Neoplastic Disorders.

Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases.

Matrix Metalloproteinases 2 and 9 Polymorphism in Patients With Myeloproliferative Diseases: A STROBE-Compliant Observational Study.

Circulating levels of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases during Japanese encephalitis virus infection.

Matrix metalloproteinases in destructive lung disease.

Targeting matrix metalloproteinases in disease conditions.

Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.

Tuberculosis, pulmonary cavitation, and matrix metalloproteinases.

A caged substrate peptide for matrix metalloproteinases.

Matrix Metalloproteinases-7 and Kidney Fibrosis.

Blepharochalasis: possibly associated with matrix metalloproteinases.

Matrix metalloproteinases as reagents for cell isolation.

The matrix metalloproteinases and their inhibitors.

Matrix metalloproteinases as therapeutic targets for stroke.

New strategies for targeting matrix metalloproteinases.

Diverse functions of matrix metalloproteinases during fibrosis.