Cardiovascular Research

Cardiovascular Research 2006 69(3):666-676; doi:10.1016/j.cardiores.2005.10.004

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Copyright © 2005, European Society of Cardiology

Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation

Anne M. Deschamps and Francis G. Spinale^*

Division of Cardiothoracic Surgery, Medical University of South Carolina, 114 Doughty Street, Room 625, Strom Thurmond Research Building, Charleston, SC 29403, United States
The Ralph H. Johnson Veteran's Association Medical Center, United States

^* Corresponding author. Division of Cardiothoracic Surgery, Medical University of South Carolina, 114 Doughty Street, Room 625, Strom Thurmond Research Building, Charleston, SC 29403, United States. Tel.: +1 843 876 5186; fax: +1 843 876 5187. Email address: wilburnm{at}musc.edu

Received 23 June 2005; revised 7 October 2005; accepted 11 October 2005

	Abstract

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
The structural basis for the development of congestive heart failure (CHF) is a maladaptive myocardial remodeling process which occurs secondarily to post-myocardial infarction (MI), hypertensive hypertrophy, or cardiomyopathy. Both cellular and extracellular factors are involved in the remodeling process and it is the combined action of these factors giving rise to changes in myocardial structure which eventually affects function. One component in this remodeling process is a family of extracellular matrix degrading enzymes, the matrix metalloproteinases or MMPs. Many bioactive molecules such as cytokines/chemokines, bioactive peptides, and neurohormones which are operative in CHF likely contribute to the induction of MMPs. For example, a specific cassette of transcription factors is likely induced with extracellular stimuli in the context of CHF which in turn induces MMPs and contributes to the maladaptive remodeling process. This review will briefly discuss the biology of the MMP family, but will more importantly identify how biological factors active in CHF result in the modulation of the MMP family. Understanding how upstream molecules are involved in MMP regulation/dysregulation may provide an avenue to develop important therapeutic interventions.

KEYWORDS Transcriptional regulation; Matrix metalloproteinases; Promoter

Abbreviations: CHF, congestive heart failure • LV, left ventricle (ventricular) • MMP, matrix metalloproteinase • MT-MMP, membrane-type MMP • TIMP, tissue inhibitor of metalloproteinases • mRNA, messenger ribonucleic acid • TNF, tumor necrosis factor-alpha • TGF-β, transforming growth factor-beta • Ang II, angiotensin II • ET, endothelin-1 • IL-1β, interleukin-1beta • OPN, osteopontin • TSP, thrombospondin • NF-B, nuclear factor kappa B • AP-1, activator protein-1 • PEA-3, polyoma enhancer A binding protein-3 • TIE, TGF-β inhibitory elements • STAT, signal transducers and activators of transcription • JAK, Janus kinase • PKC, protein kinase c • TRADD, TNFR1-associated death domain protein • RIP1, receptor interacting protein a • FADD, fas-associated death domain protein • TRAF2, TNF receptor-associated factor 2 • EGF, epidermal growth factor • ROS, reactive oxygen species

	1. Introduction

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
The structural basis for the development of congestive heart failure (CHF) is a maladaptive myocardial remodeling process which occurs secondarily to post-myocardial infarction (MI), or with hypertensive hypertrophy, or with cardiomyopathy. Both cellular and extracellular factors are involved in the remodeling process and it is the combined action of these factors giving rise to changes in myocardial structure and eventual function. One set of factors involved in this remodeling process is a family of extracellular matrix degrading enzymes, the matrix metalloproteinases (MMPs) as well as the balance of their endogenous inhibitors, TIMPs. How MMPs and TIMPs are altered in particular disease states are presented in detail in other reviews contained within this issue. While the initiating disease culminating in CHF can vary greatly, two unwavering phenomena occur as a result. First, there are a number of bioactive signaling molecules which are operative during CHF. Second, the elaboration of these molecules invariably leads to changes within the matrix. Therefore, the focus of this review will be signal transduction and transcriptional regulation of the MMP and TIMP family in response to bioactive signals operative during CHF. In this review, biological and mechanical stimuli, which alter MMP and TIMP transcriptional processes, will be examined in the context of CHF.

1.1 Transcriptional control of MMPs and TIMPs
MMPs and TIMPs are regulated at the transcriptional level by binding of transcription factors, enhancers and repressors to the gene's promoter region and their expression is modulated by external stimuli that are operative in cardiac disease states [1]. Transcription factor binding sites within MMP and TIMP promoter regions as well as key transcription factors involved in MMP and TIMP regulation have been the subject of several past reviews, however a brief examination of these subjects are discussed in the following paragraphs [1–15]. A schematic of representative MMP and TIMP promoter regions are found in Fig. 1. While MMP-2, or gelatinase A, has been demonstrated to be constitutively active in tissues at substantial levels [16] there is evidence that external stimuli can influence an additional increase in MMP-2 production [17]. Two major cis-acting elements are found in a majority of the MMP promoters–activator protein-1 (AP-1) and polyoma enhancer A binding protein-3 (PEA-3) which interact with the Fos and Jun family and Ets family of transcription factors, respectively. MMP-2 is interesting in that it lacks both the AP-1 and PEA-3 elements, and also lacks a TATA box [7]. While AP-1 and PEA-3 are found in most MMP types, there are other elements found in individual MMP promoter regions. For example, MMP-1, MMP-7, MMP-13 and MT1-MMP all have one or more TGF-β Inhibitory Elements (TIEs) which bind the family of SMAD transcription factors [2,7]. MMP-2, MMP-9, and MT1-MMP promoters contain GC boxes and bind the SP1 transcription factor [2,7]. In addition, MMP-9 has a nuclear factor-B (NF-B) binding site [7,18]. MMP-1 and MMP-13 both have been described to have an NF-B-like binding site which responds to the NF-B transcription factor [19]. All four TIMPs have one or more Sp1 binding sites, with TIMP-3 up to –500 bp from initiation only containing Sp1 sites [3–6]. Both human TIMP-1 and TIMP-2 and murine TIMP-4 have PEA-3 binding sites, while TIMP-1 and TIMP-2 have AP-1 sites [3,4,6]. In addition, murine TIMP-4 has a GATA binding site and a unique initiator-like element [6]. The different combinations of cis-binding elements as well as the interaction of trans-activating factors can provide a regional and temporal regulatory mechanism for these MMPs and TIMPs.

View larger version (37K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Transcription factor binding elements located within the proximal promoters of select MMPs and TIMPs. C/EBP-β, CCAAT enhancer-binding protein; TIE, TGF-β inhibitory element; AP-1, activator protein-1; PEA-3, polyoma enhancer A binding protein-3; OSE-2, osteoblastic cis-acting element; TATA, TATA box; AP-2, activator protein-2; Sil, silencer; GC, Sp-1 binding site; NF-B, NF-B binding site; CCAAT, CCAAT box; GATA, GATA binding site; INR, initiator-like sequence. Adapted from Refs. [1–7].

 

	2. Bioactive molecules operative in CHF

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
2.1 Renin–angiotensin–aldosterone system
Angiotensin II (Ang II) is an important mediator in cardiac remodeling associated with LV hypertrophy, following MI, and in the setting of CHF. The primary effect of Ang II is elicited through the AT1 receptor and signal transduction has been demonstrated to activate the Janus kinase–Signal Transducers and Activators of Transcription (JAK-STAT) pathways [20,21]. Transcription factors activated by this pathway include the AP-1 family of transcription factors, STATs and NF-B. Since several MMPs and TIMPs contain an AP-1 binding site and MMP-9 has an NF-B binding site in the promoter regions, Ang II can influence MMP transcription (Fig. 1). Stimulation of rat cardiac fibroblasts with Ang II induced the production of both NF-B and AP-1 transcription factors and was associated with an increase in collagen type-1 production as well as a decrease in MMP-1 expression [22]. Likewise, Ang II stimulation of neonatal rat ventricular myocytes triggered the mobilization of cytoplasmic NF-B to the nucleus which in turn increased MMP-9 transcription [23]. STAT transcription factors have been demonstrated to induce TIMP-1 mRNA in proximal tubular endothelial cells [24]. Aside from the direct actions of Ang II signaling, it has been documented that activation of G-protein-coupled receptors can transactivate the epidermal growth factor (EGF) receptor through MMP/A Disintegrin and Metalloproteinase shedding of heparin-binding EGF [25,26]. This, in turn, would activate the MAPK pathway ultimately yielding the formation of transcription factors likely inducing MMPs [27]. Thus, Ang II may cause induction of MMPs through both direct and indirect pathways.

In addition to overexpression of Ang II, increased release of aldosterone has been identified to occur in CHF and cause adverse effects [28] and aldosterone is produced locally within the failing human myocardium [29]. Like all steroids, aldosterone signals through binding to a zinc-finger intracellular receptor which translocates to the nucleus and induces transcription. Early studies have suggested that aldosterone does not have an effect on MMP production in adult rat or human cardiac fibroblasts [30,31]. However, more recent studies have demonstrated that aldosterone can affect MMP types during heart failure [32,33]. Suzuki et al. demonstrated that myocardial gelatinase (MMP-2 and MMP-9) zymographic levels were reduced in dogs with heart failure with the administration of an aldosterone antagonist [32]. In a mouse model of pressure overload it was demonstrated that MMP-2 was increased by more than 75% and this increase was attenuated with aldosterone antagonism [33]. In a more recent study, it was demonstrated that aldosterone stimulation increased MMP-2 and MMP-9 zymographic activity levels in cultured adult rat ventricular myocytes [34]. Therefore, components of the renin–angiotensin–aldosterone system result in the formation of multiple transcription factors resulting in both MMP and TIMP protein.

2.2 Oxidative stress
Oxidative stress is defined as an imbalance between oxidants and antioxidants resulting in oxidative damage to cellular and extracellular components. This process occurs in multiple pathological conditions germane to heart failure including ischemia–reperfusion and hypertrophy. Reactive oxygen and nitrogen species (ROS) arising from oxidative stress include superoxide, hydroxyl radicals, hydrogen peroxide, and peroxynitrite which in turn modify myocardial cellular and extracellular protein structure and function [35]. Of relevance to this review, ROS can alter myocardial MMPs' activational state through both transcriptional and post-translational mechanisms [36,37]. For example, ROS can directly activate pro-MMPs as well as cause the activation of key transcription factors such as NF-B, AP-1 and Ets; all of which can regulate activity [35,38,37].

There have been several in vivo and in vitro studies which have demonstrated a relationship between the generation of ROS and MMP induction [39–42]. In a clinical study, Kameda et al. demonstrated a positive correlation between a specific marker of oxidative stress (8-iso-PGF2) and relative levels of MMP-2 and MMP-9 in patients with coronary artery disease [39]. In an in vivo mouse model of MI, delivery of hydrogen peroxide increased relative MMP-2 levels whereas a ROS scavenger decreased relative MMP-2 levels [41]. However, the majority of studies evaluating the relationship between ROS exposure and MMP production have been performed in in vitro cell culture systems [40,42]. Siwik et al. demonstrated that a period of oxidative stress increased MMP-2 and MMP-9 relative abundance in a cardiac fibroblast system [40]. In human hepatic stellate cells subjected to oxidative stress, an increase in MMP-2, MT1-MMP and TIMP-2 protein occurred [42]. Processes by which oxidative stress increase transcriptional components have been studied previously in both cardiac and non-cardiac cells [43–45]. In rat ventricular myocardial fibroblasts, periods of anoxia and reoxygenation increased the expression of the transcription factor, NF-B, but had no effect on AP-1 expression [43]. The changes in these molecules could therefore lead to the modulation of MMP types regulated by these transcription factors. Moreover, it has been demonstrated that increased hydrogen peroxide production results in an increase of c-jun and c-fos mRNA and subsequent induction of MMP-1 mRNA in human skin fibroblasts [44]. A study of renal carcinoma cells identified a binding site on the promoter region of the MT1-MMP gene for hypoxia inducible factor and suggests that this transcription factor can also regulate MMP expression [45]. Taken together, these studies provide a mechanistic link between oxidative stress and the activation of MMP types in heart failure. Therefore, conditions of oxidative stress that commonly occur in cardiovascular disease states with subsequent formation of ROS are an important MMP induction mechanism.

2.3 Endothelin-1
Increased synthesis and release of endothelin (ET) has been implicated to exacerbate LV pump dysfunction in a number of cardiovascular diseases [46–48]. Fundamental intracellular events, which have been reported to occur following ET receptor activation, are the release and/or mobilization of intracellular calcium and activation of the G-protein, Gq. Activation of phospholipase C and the production of second messengers (diacylglycerol and inositol triphosphate) trigger members of the protein kinase C (PKC) family. These activated PKC isotypes are then able to activate small-G proteins such as those in the Ras and Raf family which initiate the mitogen activated protein kinase (MAPK) cascade resulting in the formation of the transcription factors c-Jun, GATA-4, a member of the Ets family, and NF-B [49]. ET has also been demonstrated to induce transactivation of the EGF receptor, which would also stimulate a signaling cascade affecting MMP expression [50].

In light of the fact that ET signaling produces c-Jun, Ets transcription factors, MMPs and TIMPs which contain an AP-1 and PEA-3 DNA binding site can be modulated (Fig. 1). Genes that contain these regions in their promoters include MMP-1, -3, -7, -9 and -13 and TIMP-1 and -4. Examples from non-cardiac cells identify a role for these transcription factors in MMP-1 regulation. For example, in vascular endothelial cells, it was demonstrated that ET could upregulate the mRNA and protein level of the transcription factor Ets-1 and that its upregulation was associated with an increase in MMP-1 levels [51]. Similarly, Naito et al. demonstrated that Ets-1 upregulation by ET increased MMP-1 mRNA in vascular smooth muscle cells [52].

	3. Sympathetic activation

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
Levels of the catecholamine, norepinephrine (NE), has been identified to be increased in patients with CHF [53,54]. NE has also been demonstrated to influence matrix remodeling through ECM turnover and MMP and TIMP induction [55,56]. NE is able to signal through both - and β-adrenergic receptor systems. NE signaling through the Gs-protein coupled β1 receptor results in the activation of adenylyl cyclase and increased cAMP levels. In addition, PKA can activate the MAPK pathway inducing other downstream responses. By extension, activation of the MAPK pathway can induce transcription factors such as c-Jun, GATA-4, and NF-B [49]. Moreover, NE is able to signal through the -adrenergic receptor system. The 1 receptor is coupled to a Gq protein and results in the activation of PLC, IP₃, DAG, and finally PKC much like that of ET signaling [57]. It has clearly been demonstrated that matrix changes do occur in response to exposure to NE. Whether these effects are directly or indirectly related to NE requires further examination.

The effect of NE on the remodeling process is demonstrated through the modulation of MMPs, TIMPs, and matrix components. A study conducted by Banfi et al., demonstrated that there was an increase in both MMP-2 and MMP-9 levels in patients with cardiomyopathy [58]. In addition, the increase in MMP-2 levels was positively correlated with norepinephrine levels. Together with in vitro cell culture studies, the authors suggest a possible link between circulating norepinephrine levels and MMP-2 activation [58]. Likewise, NE infusion in rats resulted in an increase of collagen type-I, collagen type-III, MMP-2 and TIMP-2 mRNA 3 days post-infusion [59]. Whether these effects are directly related to the actions of NE, or whether other bioactive molecules are involved remains to be determined. It is certainly possible that other bioactive molecules are involved given that NE can influence both ET and transforming growth factor-β (TGF-β) [55,57].

	4. Cytokines/chemokines

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
While a plethora of cytokines/chemokines has been identified to be activated during CHF, for the purpose of this review only two have been selected.

4.1 Tumor necrosis factor-
Tumor necrosis factor alpha (TNF) is a pleiotropic cytokine of which increased levels of TNF have been reported in patients with CHF [60,61]. TNF can bind to one of two known receptors, TNFR1 and TNFR2 [62]. Binding of TNF induces the trimerization of the TNFR and the recruitment of a number of adaptor proteins including TNFR1-associated death domain protein (TRADD), receptor-interacting protein a (RIP1), Fas-associated death domain protein (FADD) and TNF-receptor -associated factor 2 (TRAF2) [63,64]. Further signaling results in the activation of the mitogen activated protein kinases (JNK and p38) and the transcription factors of the AP-1 family and NF-B [63].

Because TNF can induce these transcription factors, it is possible that transcription of MMP-1, -3, -7, -9, and -13 and TIMP-1 and -2 could be modified. In mice, the cardiac-specific overexpression of TNF- led to progressive LV dilation and remodeling within 4–12 weeks partly due to the activation of the MMP family [65]. Specifically, Kawamura et al. examined the effects of a double transgenic mouse model in which cardiomyopathy was induced by cardiac restricted overexpression of TNF and transcription was altered due to a disrupted p50 NF-B subunit [66]. With TNF overexpression only, MMP-2 and -9 and TIMP-1 transcripts were all increased and TIMP-4 was decreased [66]. However, with the TNF overexpression and disrupted NF-B, MMP-9 levels were significantly attenuated [66]. Another study, which examined articular chondrocytes, demonstrated that TNF induced both MMP-13 mRNA and protein levels and that this induction was reduced by both AP-1 and NF-B inhibitors [67]. These studies provide a clear cause/effect relationship between TNF stimulation and transcription factor activation which in turn modify MMPs and TIMPs.

4.2 Interleukin-1β
The pro-inflammatory cytokine, interleukin-1β (IL-1β), has been demonstrated to be increased during the progression of CHF [68,69]. IL-1β can signal by binding to the IL-1 receptor containing a Toll/IL-1 receptor domain which is required for signal transduction. After ligand binding, a heterodimeric complex forms through association of two Toll/IL-1 receptor domains [70]. Next, adaptor proteins, one of which is a serine/threonine-protein kinase, are recruited to the receptor complex [70]. The serine/threonine-protein kinase then autophosphorylates and releases itself from the complex eventually causing downstream activation of the NF-B pathway [70]. In addition, IL-1β is able to activate the MAPK cascade and activate the AP-1 family of transcription factors [70].

It is therefore likely that MMP-1, -3, -7, -9, and -13 and TIMP-1 and -2 can be regulated by IL-1β. IL-1β has been demonstrated to increase both NF-B and AP-1 DNA binding in neonatal rat myocytes [69]. Stimulation of adult rat cardiac fibroblasts with IL-1β induced an upregulation of both MMP-2 and MMP-9 protein levels and this increase was reduced with an NF-B inhibitor suggesting a role for this transcription factor in MMP regulation [71]. A limited number of studies have looked at the role of the AP-1 family of transcription factors in cardiac cells, or in animal models of myocardial injury in response to IL-1β stimulation. However, a study utilizing human gingival fibroblasts demonstrated that IL-1β induced c-jun and c-fos expression which was reduced with specific MAPK inhibitors [72]. Additionally, MMP-1 levels were increased with IL-1β stimulation and were effectively attenuated with MAPK inhibitors suggesting a role for AP-1 in MMP-1 gene induction [72].

	5. Matricellular factors in CHF

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
5.1 Osteopontin
Osteopontin (OPN) can function as both a cell attachment molecule as well as a cytokine. While OPN is highly expressed during embryonic development, OPN expression in the adult human heart is quite low. However, following a pathophysiological stimulus such as myocardial infarction or increased LV afterload, OPN levels increase rapidly and robustly [73]. OPN appears to have a multiplicity of effects which include modulating fibroblast and myocyte adhesion to the matrix, matrix synthesis, and synergism with other profibrotic molecules. Several studies have been published which have demonstrated that in transgenic mice devoid of the OPN gene, the hypertrophic response and the exuberant matrix accumulation was attenuated in models of aortic banding or Ang II infusion [74–76]. Binding of OPN to the vβ3 integrin results in the production of the NF-B transcription factor [77] and AP-1 activation [78]. Additionally, signaling through CD44 results in the activation of the PI3K/AKT pathway [79] and NF-B [80].

Due to the fact that NF-B is produced through OPN signaling, it would identify MMP-1, -9, and -13 as candidate genes for regulation (Fig. 1). Two studies have demonstrated that OPN can induce MMP-2 and MMP-9 activation through an NF-B dependent mechanism [77,81,82]. In addition, it has been demonstrated that OPN is increased following ischemia–reperfusion, which may provide a mechanistic link for the induction of MMP-2 and MMP-9 in this process [83]. Conversely, it has been shown that OPN can reduce the increased MMP expression and activation associated with IL-1β stimulation in adult rat cardiac fibroblasts [84]. Therefore, it is likely that OPN influences MMP/TIMP transcription in cardiovascular disease states.

5.2 Transforming growth factor-β
The transforming growth factor (TGF) superfamily is comprised of more than 30 members that have a wide range of functions during development, cell cycle control and growth, extracellular matrix regulation, and immune response [85]. TGF-β1 is the most abundant and well studied of the three TGF-β isoforms and will be the focus of this section. TGF-β has been demonstrated to be increased during heart failure and contributes to the hypertrophy of myocytes and fibrosis [86]. During CHF, TGF-β can induce a signaling cascade through binding to the serine/threonine kinase receptors, TGF-βRI and II. Binding of TGF-β to the type I receptor causes the type II receptor to translocate and form a heteromeric complex. The type I receptor is phosphorylated by the type II receptor which in turn phosphorylates R-SMADs. These proteins subsequently dimerize and translocate to the nucleus and bind to the TIE promoter region in turn inducing transcriptional activation of specific target genes.

Given that MMP-1, -7 and MT1-MMP have TIE binding domains in their promoter, it is suggestive that these MMP types might be altered with increased levels of TGF-β. In addition, it has been demonstrated that SMADs can directly interact with members of the AP-1 family of transcription factors thereby increasing the possible number of promoter interactions [87,88]. A study by Hall et al. examined MMP-1 and TIMP-1 expression in fibroblasts after stimulation with TGF-β [89]. The authors demonstrated that the proximal AP-1 site is essential for both the induction of TIMP-1 and repression of MMP-1 [89]. In addition, it has been demonstrated that MMP-1 repression is mediated through the SMAD3 and SMAD4 activation in dermal fibroblasts [90]. Taken together, these studies provide a mechanism for the fibrotic process associated with TGF-β stimulation.

5.3 Transmembrane ligand systems
5.3.1 Thrombospondin
Thrombospondins (TSPs) are a family of secreted glycoproteins that appear to modulate cell/matrix interactions through the coalescence of membrane proteins and signaling molecules at specific contact points on the cell surface [91,92]. TSP-2 and TSP-4 have been shown to be upregulated in the transition from myocardial hypertrophy to failure in renin overexpressing rats and spontaneously hypertensive rats, respectively [93,94]. In addition TSP-2 null mice show abnormalities in matrix structure and composition [95]. TSPs have been identified to signal through a number of receptors including CD36, CD47 and integrins [92]. While the transduction pathway following TSP binding may be diverse, one likely event is the production of AP-1 transcription factors [96–98]. Thus MMPs/TIMPs which have AP-1 binding sites are likely to be modified with TSP stimulation. Fibroblasts cultured from TSP-2 null mice demonstrated altered levels of MMP-2 [95,99,100]. In addition, depending on the fragment of TSP used to stimulate bovine post capillary endothelial cells, a differential production of MMP-2, -9 and TIMP-2 occurred [98].

5.3.2 EMMPRIN
EMMPRIN (extracellular matrix metalloproteinase inducer; a.k.a. basigin and CD147) is a 58-kDa, membrane-bound glycoprotein of the Ig superfamily that has been identified in both normal and diseased human tissue [101,102]. A past study demonstrated increased abundance of EMMPRIN in DCM myocardium [103]. While the signaling pathway for EMMPRIN induced MMP activation has not been fully discerned, it has been demonstrated that EMMPRIN does signal in MAPK p38 dependent manner for MMP-1 and through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway for MMP-2 [104,105]. Interestingly, in vitro studies have demonstrated that although EMMPRIN induced MMP expression, it did not influence the basal expression of TIMP-1 [106]. A similar pattern of expression has been observed with cardiomyopathy in which increased EMMPRIN levels were associated with increased levels of certain MMP species but in which TIMP-1 levels remained unchanged or actually decreased [103,107,108].

	6. Mechanical signaling

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
Alterations in mechanical stretch and strain occur primarily in response to changes in hemodynamic load. One mechanism by which changes in stress and strain are manifested is through a class of transmembrane proteins, the integrins. The integrins are a family of heterodimeric proteins that traverse the cell membrane and link the extracellular matrix to its cytoplasmic actin cytoskeleton. Integrins were initially thought to function as matrix-cytoskeleton attachment molecules but have since been shown to play a number of roles in cell–matrix behaviors particularly signal transduction [109].

Integrin-mediated signaling activates protein tyrosine kinases such as focal adhesion kinase and Src and results in the activation of the ERK2 and JNK1 pathways which in turn activate transcription factors relevant to MMP transcriptional regulation [109,110]. Consistent with this, a study conducted by van Wamel et al. subjected rat cardiac myocytes and fibroblasts to static stretch and demonstrated that components of the AP-1 heterodimeric complex were altered in a time dependent manner [111]. Independent of AP-1 regulated transcription regulation, Wang et al. examined the effect of stretch induced changes in Ang II and MMP levels [112]. The authors demonstrated that MT1-MMP and MMP-2 expression in neonatal rat cardiomyocytes is mediated through STAT1 [112]. Therefore, mechanical signals likely transduced through integrins likely contribute to the transcriptional regulation of MMPs.

	7. Summary and future directions

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 
The purpose of this review was not to comprehensively integrate all of the biological stimuli which can cause the induction of MMPs, but rather to focus on specific signaling pathways which would likely be operative in the context of CHF. However, it must be recognized that the signals and pathways described in the preceding pages are likely differentially induced depending on the cardiac disease state. Thus, significant generalizations have been taken into how these biological stimuli can alter MMP/TIMP transcription. Furthermore, it must be recognized that these pathways do not work in isolation but rather in a dynamic state within the myocardial interstitium. For example, a study by Rude et al. demonstrated that stimulation of adult rat ventricular myocytes with aldosterone increased ROS production and further activation of MMP-2 and -9 [34]. In addition, Tsuruda et al. showed differential results in MMP induction with a combination of biological stimuli [113]. Thus, there are numerous signals that give rise to intracellular transduction pathways and formation of transcription factors which are integrated and eventually drive MMP transcription (Fig. 2). Whether and to what degree one, several, or all of these pathways play a dominant role in MMP induction is dependent upon the initiating disease–myocardial infarction, hypertensive hypertrophy, or cardiomyopathy.

View larger version (64K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Schematic demonstrating the multiple signaling pathways induced during CHF. There are numerous signals that give rise to a multitude of transduction pathways and transcription factors which are integrated and eventually drive MMP transcription. Whether and to what degree one, several, or all of these pathways play a dominant role in MMP induction is dependent upon the initiating disease–myocardial infarction, hypertensive hypertrophy, or cardiomyopathy. ANGII, angiotensin II; IL-1β, interleukin-1beta; OPN, osteopontin; TSP, thrombospondin; TGFβ, transforming growth factor beta; TNF, tumor necrosis factor; ALDO, aldosterone; ROS, reactive oxygen species.

 
Strategies to modify transcriptional activity of MMP/TIMPs would include antagonizing the transmembrane receptor domains–but due to the significant number of receptor systems and pathways that can increase transcriptional activity, this would require a poly-pharmaceutical approach. Another strategy would be to alter the intracellular trafficking of common signaling pathways involved in MMP/TIMP transcription. For example, a number of neurohormonal signaling pathways evoke PKC activation that in turn induces transcription factor formation and binding to MMP gene promoter sequences. It is now known that PKC activation and translocation to an effector target site are dependent upon specific protein sequences that are highly selective for PKC isoforms [114–116]. These intracellular receptors for activated PKC, RACK proteins (receptors for activated C-kinase), have been sequenced and cloned [114–116]. Studies have demonstrated that small peptide fragments corresponding to the RACK binding site of each PKC isoform can result in selective loss of function of the isozymes [114–116]. Therefore, small molecule strategies that target and inhibit specific PKC isoforms would in turn likely reduce MMP transcriptional events. Another strategy would be to interrupt the synthesis of transcription factors causative in the induction of certain MMPs or TIMPs. For example, RNA interference (RNAi) is a process by which post-transcriptional silencing of targeted mRNAs is achieved through the introduction of a complementary RNA sequence [117,118]. It has been demonstrated that transfection of mammalian cells with a double strand RNAi sequence specifically binds to a targeted mRNA preventing translation and promoting transcript degradation [119–121]. For example, transfection of a DNA vector encoding for an RNAi which targeted the STAT transcription factor effectively silenced STAT transcription in a nude mouse model [119]. In addition to using the RNAi technique to silence transcription factors operative in MMP/TIMP expression, this approach may also be applicable in targeting specific MMP/TIMP transcripts directly [120,121]. For example, using adenoviral construct and transfection methods, an RNAi sequence targeted against the MMP-9 mRNA was produced in mammalian cells (glioblastoma cell line) [120]. In this study, significant inhibition of MMP-9 zymographic activity and indices of in vitro matrix remodeling were achieved through overexpression of a specific RNAi. Thus, while significant issues regarding delivery, stability, and construct design remain to be established, future strategies which target pre-translational events may hold promise as a specific means to regulate myocardial MMP/TIMP expression.

	Acknowledgements

 
This study was supported by NIH Grants HL59165, P01 HL48788-08, and a Career Development Award from the Ralph H. Johnson Veterans' Association Medical Center. The authors would also like to acknowledge I. Matthew Mains for his assistance with the manuscript.

	Notes

 
Time for primary review 25 days

	References

Top Abstract 1. Introduction 2. Bioactive molecules operative... 3. Sympathetic activation 4. Cytokines/chemokines 5. Matricellular factors in... 6. Mechanical signaling 7. Summary and future... References

 

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