Abstract

Recently, it has been demonstrated that myocardial inflammation plays a pivotal role in the development and progression of congestive heart failure. The myocardial inflammatory reaction not only affects myocardial hypertrophy and apoptosis, but it has a major influence on the regulation of extracellular matrix turnover. The balance between collagen synthesis and degradation is of crucial relevance in maintaining the structural integrity of the heart. Therefore, the overwhelming inflammatory response, as seen in acute myocarditis or inflammatory cardiomyopathy, could lead to a breakdown of this tightly regulated system. This is an additional key factor in the development and progression of heart failure.

This review summarizes the importance of myocardial inflammation in respect to extracellular matrix remodeling and its possible patho-physiological role in the development and progression of left ventricular dysfunction in inflammatory heart disease.

1. Introduction

Myocarditis, an inflammatory disorder, which is most commonly caused by viral infection (especially enterovirus and parvovirus), is associated with acute left ventricular dysfunction accompanied by myocardial inflammatory cell infiltration and increased release of proinflammatory cytokines [1]. The presence of viral genome in endomyocardial biopsies of patients with dilated cardiomyopathy (DCM) demonstrates an interrelationship between acute myocarditis and DCM [2–4]. A similar frequency of intramyocardial inflammation was found in patients with DCM, which reflects the relevance of chronic inflammation in the development of left ventricular dysfunction [5]. However, not only viral persistence and chronic inflammatory response seem to play an important role in the pathogenesis of inflammatory cardiomyopathy. The latest investigations advert to a momentous role of matrix metalloproteinases in the disruption of the extracellular matrix (ECM) architecture involving a pathological elevated myocardial collagen turnover which leads to the loss of structural integrity of the heart resulting in left ventricular dysfunction [1,6–8]. In the latest investigations these factors have been shown to play a crucial role in the disruption of the ECM architecture. A pathologically elevated myocardial collagen turnover leads to the loss of structural integrity of the heart and ensuing left ventricular dysfunction.

Acute left ventricular dysfunction in experimental induced acute myocarditis is associated with induction of proinflammatory cytokines and an imbalance of the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) system [1]. Proinflammatory cytokines like TNF-α and IL-1β contribute not only to depression of LV function and cardiomyocyte loss by apoptosis, they also play a critical role in maintaining the balance in ECM-remodeling [9–11], showing the importance of chronic inflammation in myocardial remodeling process as well as in the development of DCM [12]. They regulate cardiac fibroblast function with the expression of collagen types I and III and fibronectin, and moreover also regulate the matrix degradation system by influencing the expression of matrix metalloproteinases (MMPs), the tissue inhibitors of MMPs (TIMPs) and their activators like urokinase type plasminogen activator and tissue type plasminogen activator (uPA, tPA) [12–15]. This seems to indicate that the maintenance of the physiological myocardial matrix turnover involves a highly regulated interaction between cardiac and noncardiac cells, in response to the release of inflammatory mediators and components of the matrix degradation system.

Heart failure and cytokines

Chronic heart failure is a disease with multiple causes of which an inflammatory reaction is the most important. Over the past years inflammatory cytokines and neurohormones have been shown to contribute to the development and progression of left ventricular dysfunction. Congestive heart failure is now commonly seen as a state of chronic inflammation. Proinflammatory cytokines like TNF-α and IL-6 are elevated in different entities of heart failure like acute myocardial infarction, stable angina pectoris or acute myocarditis with perpetuation of congestive heart failure and relevance for prognosis of the disease [16–19]. For instance, TNF-α has been shown to induce myocardial hypertrophy and fibrosis [20], increase cardiac myocyte apoptosis and induce activation of the inducible form of nitric oxide synthase (iNOS) [21]. IL-1 has been demonstrated to depress myocardial contractility in a dose-dependent manner and to contribute to myocardial apoptosis and hypertrophy. In collaboration with IL-1β, TNF-α also promotes Coxsackievirus B3-myocarditis in resistant Balb/c-mice [22]. In our previous investigations we could show a close correlation between the development of left ventricular dysfunction and the increase of myocardial mRNA abundance of IL-1β and TNF-α in a murine model of CVB-3 induced acute myocarditis (Fig. 1). Furthermore, Liu and Zhao have demonstrated that heart function is improved by declining circulating TNF-α concentration [23]. The neurohumoral activation and the elevated oxidative stress during the development of left ventricular dysfunction in congestive heart failure can be triggered by proinflammatory cytokines. Increased free oxidative radicals are able to lead to an activation of p38-MAP-kinase and nuclear factor kappa B (NFκB). These directly affect left ventricular dysfunction by inducing cardiomycytolysis and by the negative inotropic effects of reduced calcium uptake by the sarcoplasmatic reticulum [24,25]. Another important pathophysiologic process in the development of congestive heart failure concerns the sympathic nervous system with increased levels of catecholamines, which may result in an overwhelming inflammatory reaction. Murray et al. have demonstrated that chronic β-adrenergic stimulation leads to an increase of myocardial gene expression and protein production of TNF-α, IL-1β and IL-6 [26]. This result confirms previous studies showing that isoproterenol advances myocardial hypertrophy [27], myocyte degeneration and inflammatory cell infiltration [28]. This is also in line with our investigation, as described below, which shows that the treatment of acute myocarditis with a β-adrenergic receptor blocker leads to a reduced inflammatory response, modulated immune reaction and decreased ECM remodeling as well as an improved left ventricular function [29].

Fig. 1

(a) Significant correlation between myocardial mRNA abundance of IL-1β and left ventricular endsystolic pressure (LVESP) in a murine model of Coxsackievirus B3 induced acute myocarditis. R2>0.5 were considered as significant; p<0.001. (b) Significant correlation between myocardial mRNA abundance of TNF-α and left ventricular endsystolic pressure (LVESP) in a murine model of Coxsackievirus B3 induced acute myocarditis. R2>0.5 were considered as significant; p<0.001.

Fig. 1

(a) Significant correlation between myocardial mRNA abundance of IL-1β and left ventricular endsystolic pressure (LVESP) in a murine model of Coxsackievirus B3 induced acute myocarditis. R2>0.5 were considered as significant; p<0.001. (b) Significant correlation between myocardial mRNA abundance of TNF-α and left ventricular endsystolic pressure (LVESP) in a murine model of Coxsackievirus B3 induced acute myocarditis. R2>0.5 were considered as significant; p<0.001.

Myocarditis and dilated cardiomyopathy

Myocarditis, an inflammatory disease of the myocardium, diagnosed by standardized histological and immunohistological methods [30], is caused by both infectious and noninfectious agents [31]. However, the main cause is the viral infection of the myocardium with cardiotropic viruses, like enterovirus or parvovirus [32]. Previous investigations on endomyocardial biopsies showed that several other viral agents like adenovirus or parvovirus B19 are also involved in the etiology of myocarditis [3,4]. For the pathogenesis of myocarditis, Kawai described a triphasic model with an acute, subacute and chronic phase [33]. During the acute phase the myocardium mainly expresses proinflammatory cytokines, such as IL-1β, TNF-α and Interferon-γ [34,35]. These elevated proinflammatory cytokine levels are linked to histological changes such as myocyte necrosis and apoptosis [36,37]. In this early stage of disease there is very little infiltration of natural killer cells and macrophages in the myocardium [38,39]. This phase is characterized by a dominance of direct pathogenicity of viral action and myocyte apoptosis with direct alteration of myocardial architecture by destroying dystrophin [40–43]. In the subacute phase an increase in myocardial cell infiltration, especially T-lymphocytes, natural killer cells and fibroblasts follows [33]. The protective effect of natural killer cells is based on their suppression of viral replication by the perforin-induced disturbance of infected cardiomyocytes [44,45]. The importance of early suppression of viral replication is shown by the more severe myocarditis seen in a murine myocarditis model with a defect of NK-cells [46]. Seko et al. could detect a time-dependent release of cytokines, with an initial increase of proinflammatory cytokines (IL-1β, IL-6, TNF-α, Interferon-γ) to the 7th day after infection, followed by regulatory cytokines like IL-2, IL-4 and IL-10 [47]. The outcome of the virus-induced immune response is not straightforward and may vary greatly. An efficient viral elimination through a radical immune response is required for a better outcome of the disease. For example, patients with myocarditis who have higher cardiac specific IgG have better survival prospects [48] and furthermore, acute fulminant myocarditis with an initial massive inflammation and more pronounced cellular injury has a better long-term outcome as compared with acute nonfulminant myocarditis [49]. On the other hand an uncontrolled immune response is associated with an inefficient viral elimination, pathological myocardial inflammation, and initiating of cross-reacting antibodies, which result in progressive cellular injury and matrix remodeling. The increase of cardiac cell-infiltration and release of inflammatory cytokines directly correlate to the development of left ventricular dysfunction [50]. Viral persistence and chronic inflammation may finally lead to the third and chronic phase of myocarditis with the development of dilated cardiomyopathy. Enteroviral genome could be detected in the myocardium up to 90 days after viral infection in a murine model of myocarditis, which indicates one causal step of chronic myocardial cell infiltration [51,52]. The importance of latent or persistent virus with induced chronic myocardial inflammation has been demonstrated in persistent Cytomegalovirus-myocarditis [53] and in the development of left ventricular dilatation in mice with persistence of Coxsackievirus B3 [54]. The presence of viral genome in endomyocardial biopsies of patients with dilated cardiomyopathy underlines the relationship between myocarditis and the development of left ventricular dysfunction [2]. Another important step in the development and progression of acute left ventricular dysfunction and dilatation is the initiation of an adverse remodeling of the ECM by immune mediators. Chronic myocardial inflammation induces the pathological collagen turnover resulting in loss of structural integrity of the myocardium and in the development of left ventricular dysfunction.

The extracellular matrix–collagen and cytokines

Myocardial ECM (mainly collagen type I and III and fibronectin, elastin, etc.) forms a three dimensional cross-linked collagen-network which supports the cellular and structural integrity of the heart. After secretion into the ECM, the fibril-forming collagens aggregate spontaneously after following the processing of procollagens into ordered fibrillar network, stabilized by covalent cross-links. The structural elements are dynamic and there is a complex network of receptors and enzymes within the ECM which controls the turnover of this tightly regulated system. Collagen production and degradation is an important process in the development of left ventricular dysfunction in acute and chronic myocarditis and determines the maintenance of cardiac architecture.

Collagen synthesis by cardiac fibroblasts is regulated by multiple factors, including inflammatory cytokines like TNF-α, IL-1β or TGF-β, TNF-α and IL-1β have been shown to decrease the expression of procollagen type I and III and increase the expression of fibronectin and nonfibrillar procollagen type IV. Furthermore, several other factors like aldosterone, TGF-β or mechanical stretch have been shown to induce the mRNA synthesis of collagen [12]. The renin-angiotensine-system also partakes in the regulation of collagen synthesis; angiotensin II induces ECM protein synthesis and accumulation via AT1-receptor stimulation, effects that are mediated by TGF-β1 and endothelin-1 [55]. A rat model of myocardial infarction showed the importance of this myocardial remodeling: ACE inhibition prevented collagen accumulation and DNA synthesis and furthermore completely inhibited collagen deposition with AT1-receptor antagonism [56].

Fibrillar collagen turnover results from the equilibrium between the synthesis and the degradation of collagen, mainly types I and III. In the healthy left ventricle ECM replacement is about 5% to 9%, in pathological conditions, e.g. after myocardial infarction, this figure can rise to 50% [57]. Furthermore the rate of collagen synthesis per day is much slower than of noncollagen proteins with a longer half-life period of collagen, implying a fairly slow ECM replacement after degradation and potential vulnerability for adverse remodeling [58]. This additionally reduces the ability to form the three dimensional network with collagen cross-links, which leads to alteration in the composition and structure of myocardial collagen.

The MMP system

Collagen degradation is an important step in ECM remodeling, mainly due to matrix metalloproteinases (MMPs) and serine-proteinases. The matrix metalloproteinases are a family of 20 different species of zinc-dependent enzymes [59], which could be expressed under basal conditions by fibroblasts and myocytes and also in response to inflammatory reactions by infiltrating macrophages and lymphocytes. One group of MMPs is secreted into the extracellular space in a latent or proenzyme form and the other group is membrane-bound. Regarding the catalytic domain of MMPs, a large extracellular binding domain at the C-terminus is responsible for the substrate specificity and the specific binding to ECM proteins [59,60]. In addition, these substrate specificities and functions classify the secreted MMPs in three different groups. First the collagenases (MMP-1, MMP-8, MMP-13) decompose the insoluble collagen fibrils into soluble fragments [61]. The cleaving of these soluble fragments is continued by gelatinases (MMP-2, MMP-9), which are highly expressed in the left ventricular myocardium [7,62]. Coker et al. showed an isolated expression of these gelatinases in LV-myocytes, which supports the possibility of a direct processing of matrix remodeling by the synthesis and release of MMPs [63]. MMP-2 is thereby constitutively expressed in the myocardium, whereas MMP-9 is an inducible form of the MMPs and becomes more relevant under inflammation with inducible expression in neutrophils and macrophages [64,65]. The third group, the stromelysine-like MMP-3, degrades not only a wide range of components of the ECM, it can also initiate the activation of the inactive pro-MMPs.

The group of membrane-bound MMPs (Membrane Type-MMP, MT-MMP) plays also a critical role in matrix remodeling, which on the one hand cleaves intact fibrillar collagen and basement membrane components and on the other hand directly activates different pro-MMPs [66]. However MMPs do not only play a role in the degradation of the ECM-components, the final fragmented matrix peptides also have biological activities and have been shown to stimulate new collagen synthesis by cardiac fibroblasts [67].

Beside the ECM components, the target substrates of the MMPs also include nonmatrix proteins such as cytokines, receptors and adhesions molecules [68–70]. This explains additional functions of MMPs as for example regulating growth, cell pathways, and angiogenesis [71]. The capability of activated MMPs to degrade the complete ECM is conditioned by a tightly controlled system. First, the control at the transcriptional level by several cytokines or growth factors; second the control of pro-MMP activation by serine proteinases (Plasmin-system), MT-MMPs or stromelysines; and last the inhibition of activated MMPs by the tissue inhibitors of MMPs (TIMP1-4) (Fig. 2).

Fig. 2

Simplified mechanism of regulation in the Matrix-Degradation-System. Importance of inflammatory mediators.

Fig. 2

Simplified mechanism of regulation in the Matrix-Degradation-System. Importance of inflammatory mediators.

Synthesis of MMPs

The synthesis of MMPs at the transcriptional level is influenced by multiple cytokines, neurohormones and growth factors [72]. Different signaling pathways have been shown to be involved in regulation of the expression of MMPs [73–80].

It could be demonstrated that proinflammatory cytokines like IL-1β, TNF-α or IL-6 induce MMP-synthesis [12,13]. Furthermore, in mice with over expressing TNF-α, a progressive development of left ventricular dilatation is associated with increased MMP-activity [20]. In collaboration with TNF-α, interferon-γ enhances the MMP-1 synthesis in human monocytes and neutralizing antibodies against TNF-α block the induction of MMP-1 by interferon-γ [81]. By contrast, TGF-β1 on the one hand decreases the proteolytic activity of MMP-1 and MMP-3 by suppressing MMP gene expression through the TGF-β inhibitory element (TIE) and on the other hand increases the expression of MMP-2 and MMP-9 [14,82]. Beside inflammatory cytokines, several other bioactive molecules also influence the synthesis of MMPs. Angiotensin II plays a pivotal role here: It has been demonstrated that angiotensin II induces the expression of MMP-2, -9 and -14 in neonatal rat fibroblast [83]. Its importance in this regulating process is further shown by an improvement in left ventricular function and myocardial geometry through reduced MMP-synthesis after ACE-inhibition or AT-1 blockade [84,85]. Endothelin-1 enhances the production of MMP-2 and MMP-9 and endothelin receptor blockade results in reduced levels of MMP-2 and -9 [86]. Furthermore, natriuretic peptides like BNP (brain natriuretic peptide) are able to induce the MMP-synthesis in chronic heart failure and myocardial remodeling [87].

Activation of MMPs

MT-MMPs and MMP-3 activate different members of the MMP family by proteolytic cleavage of the MMP-propeptide [15,66,88]. Even more important is the plasminogen system (plasminogen activators (PA), tissue-type PA (t-PA), urokinase-type PA (uPA) and the PA-inhibitor (PAI)), which activates the inactive proMMPs as described above [88]. The importance of this system in disrupting the cardiac collagen network has been previously demonstrated in mice lacking uPA or mice with acute pressure overload with PAI gene transfer showing improved left ventricular function with reduced myocardial fibrosis and preserved interstitial matrix [89]. Beside MMP-activation the PA are also able to cleave matrix proteins like fibrin and fibronectin. The expression of uPA [90], which has the same transcription factor binding elements (AP-1, PEA3) in the promotor region like MMP-1 and MMP-3 is induced by IL-1β and TNF-α [91]. In fibroblasts, IL-1β increases not only the protein and mRNA expression of uPA but also its receptor uPAR [92]. Furthermore, there is a feedback regulation between the MMPs and the plasmin-system; MMP-3 has been demonstrated to cleave their physiological inhibitor (PAI, α2-antiplasmin) resulting in neutralization [93,94].

Inhibition of MMPs

Active MMPs are specifically inhibited by their endogenous inhibitors, the TIMPs that are composed of four subtypes (TIMP-1-4) [81,95–97]. TIMPs bind to the active site of MMP in a 1:1 stoichiometrie, blocking their access to collagen substrate [15,98]. Furthermore they can bind latent MMPs at the aminoterminus thereby preventing their activation [99]. Some differences in the inhibitory properties of the different TIMPs have been reported. TIMP-2 and TIMP-3 have been proven to be effective inhibitors of membrane-bound-MMPs, and TIMP-3 is the only TIMP which can inhibit TNF-α converting enzyme [100,101]. Mice deficient of TIMP-1 gene develop increased left ventricular mass and increased end diastolic volume suggesting its important role in the prevented activation of the protease cascade and in the maintenance of a dynamic matrix balance. Inflammatory mediators also influence this third step in the control of MMP-activity; IL-1 and TNF-α can down regulate the expression of TIMP-1 [15]. Beside this specific inhibition α2 macroglubulin and heparin nonspecifically inhibit MMP-activity [102,103].

This widespread influence of inflammatory reaction on the regulation of the matrix degradation system reflects a deregulation in disease with pathologically elevated inflammatory mediators.

Extracellular matrix remodeling

ECM in acute myocarditis

Our previous investigations focused on the inflammatory reaction in virus-induced acute myocarditis caused by disruption of the collagen turnover and the resulting changes in the ECM and its influence on left ventricular dysfunction [1]. We could show that in the early phase of myocarditis the main disruption of ECM is caused by qualitative changes in the collagen network. Expression of myocardial mRNA and protein abundance of collagen type I was unchanged as was total collagen content measured by picrosirius red staining. However Western blot analysis demonstrated an increased fraction of soluble collagen, suggesting an initial dominance of posttranslational collagen variation contingent on an imbalance in the matrix degradation system. Corroborating these findings, Woodiwiss et al. have demonstrated that a reduction in collagen cross-links is responsible for the decreased native insoluble or increased soluble collagen and is associated with left ventricular dysfunction, remodeling and chamber dilatation [104]. MMP-9, which depolimerizes the cross-linked polymers of collagen type I [105], seems to play an important role. Furthermore, LV enlargement after myocardial infarction could be prevented by deletion of the MMP-9 gene [106]. CVB-3 infection of the myocardium caused a significant release of proinflammatory cytokines such as IL-1β, TNF-α and TGF-β on the 10th day post infection. This was accompanied by an up regulated expression of MMP-3 and MMP-9 and reduced levels of their endogenous specific inhibitors TIMP-1 and TIMP-4. Furthermore, our unpublished data show evidence of an imbalance in the plasmin regulation system in this acute early phase of myocarditis by significant induced mRNA abundance of uPA with simultaneously reduced levels of PAI mRNA abundance (Fig. 3). As described above, a restored interstitial matrix with an undilated chamber could be demonstrated in a uPA knock-out model of chronic volume overload [89], suggesting that the above demonstrated imbalance in the matrix degradation system was mainly responsible for the development of left ventricular dysfunction. Increased levels of MMPs, decreased levels of TIMPs and the activated plasmin system in the acute phase of myocarditis may lead to an imbalance in the matrix degradation system in favour of matrix protein degradation. This ultimately reduces the matrix integrity and disrupts the three dimensional collagen network by cleaving the cross-links between the collagen molecules, which then leads to left ventricular dysfunction and dilatation.

Fig. 3

Differential mRNA abundances of myocardial MMP-3, TIMP-1, PAI and uPA and gelatinase activity in acute myocarditis on 10th day postinfection. Dominance of matrix degrading components with loss of their controlling agents. *p<0.05 were considered as significant.

Fig. 3

Differential mRNA abundances of myocardial MMP-3, TIMP-1, PAI and uPA and gelatinase activity in acute myocarditis on 10th day postinfection. Dominance of matrix degrading components with loss of their controlling agents. *p<0.05 were considered as significant.

ECM in dilated cardiomyopathy

As described above, previous investigations suggested an association between myocarditis and inflammatory cardiomyopathy caused by viral persistence. Signs are dystrophin degradation, myocardial inflammation with cytotoxic T-lymphocyte-mediated myocytolysis, B-lymphocyte-mediated generation of autoantibodies and induction of the MMP-system with pathologic collagen degradation and left ventricular dilatation. The results of our recent analysis of endomyocardial biopsies emphasize the importance of persistent inflammation in dilated cardiomyopathy regarding ECM alterations and the development of left ventricular dysfunction. The myocardial mRNA abundance of MMP-3 and TIMP-1 was analyzed in endomyocardial biopsies of patients with dilated cardiomyopathy with or without inflammation and in biopsies of patients with normal left ventricular function without histological signs of inflammation. We could demonstrate a significantly induced expression of myocardial MMP-3 in inflammatory cardiomyopathy accompanied by a reduced expression of TIMP-4 [107] in dilated cardiomyopathy without inflammation. This is in line with the results of Schwartzkopff et al. who have shown elevated serum markers of collagen degradation accompanied by increased levels of MMP-1 in patients with DCM [108]. Furthermore there was a negative correlation between the MMP/TIMP ratio and the degree of LV-dilatation, underlining the importance of collagen degradation in the development of left ventricular dysfunction. Moreover, we could detect a co-localization of CD-3 and MMP-3, measured by immune histochemistry, which further emphasizes the importance of inflammation in this pathogenesis.

The increased production of collagen in the later stage of myocarditis seems to be a response to collagen degradation caused by increased MMP-activity. Since matrikines enhance the synthesis of procollagen it might be possible that after the initial importance of degradation, fibrosis takes over in the later phase of myocarditis [58]. This was also verified by Pauschinger et al. in patients with DCM, who had an increase in the myocardial collagen content measured by picrosirius red staining [8]. McCormick et al. speculated that there was a defect in collagen cross-linking pathways, leading to an increase in collagen concentration and collagenase activity with ventricular dilatation since in patients with idiopathic dilated cardiomyopathy, collagen deposition was doubled but hydroxyproline concentration was reduced [109,110]. Furthermore a prospective study on serum markers of collagen metabolism in idiopathic DCM showed that patients with increased serum markers had an increased risk for transplantation, impaired left ventricular function, or advanced clinical stage of heart failure, and death suggesting that increased collagen synthesis and degradation act as a factor in risk stratification [111].

During the fibrotic process, the collagen accumulation was also accompanied by a change in the ratio of Collagen I and III, suggesting increased myocardial stiffness with impaired systolic and diastolic function [8].

Kühl et al. have demonstrated an improved left ventricular function by eliminating viral persistence (Adenovirus and Enterovirus) through therapy with Interferon-β [112]. In this study the viral elimination led to significantly reduced inflammation, which furthermore reflects the pivotal role of viral persistence and chronic induced inflammation. Kühl et al. also suggest that active viral replication interferes with inflammatory cytokine release as well as with matrix integrity. This may be partially reversible after viral elimination and could explain improved cardiac function after viral elimination. Further analysis will show whether the possibly reduced pathological alterations of the MMP/TIMP system in response to myocardial collagen deposition play a role in the development of improved left ventricular dysfunction after viral elimination through β-interferon.

ECM-remodeling in acute myocarditis with β-adrenergic-blockage

In order to explore the influence of induced sympathic activity and oxidative stress on cardiac inflammatory reaction we investigated the effect of a β-adrenergic-blockage on a possible improvement of myocardial injury and imbalance in the MMP/TIMP-system [29]. The effects of carvedilol and metoprolol on myocardial inflammation, ECM remodeling and left ventricular function were examined in hearts of Coxsackievirus B3 infected Balb/c mice on the 10th day after infection. Carvedilol could improve left ventricular dysfunction with a significant enhancement of LVESP, dP/dtmax and dP/dtmin[113]. This improvement was accompanied by a reduced inflammatory reaction as shown by the reduced release of proinflammatory cytokines such as IL-1β, TNF-α and TGF-β. The importance of proinflammatory cytokines in the development of left ventricular function was demonstrated by a significant correlation between the myocardial enlargement caused by proinflammatory cytokines and cardiac hemodynamic parameters. We could furthermore show an improved balance of the MMP/TIMP-system with reduced levels of myocardial mRNA abundance of MMPs, especially MMP-8, reflecting a reduced myocardial cell infiltration by the cell specific expression of neutrophils underlined by its significant correlation to the regulation of IL-1β, TNF-α. This emphasizes the complex interaction of ECM remodeling, neurohumoral activation, reactive oxygen species, myocardial cell infiltration and release of proinflammatory cytokines. A comparison between carvedilol and metoprolol showed that carvedilol exerts a better effect in the improvement of left ventricular function. This might be due to the absent effect of the selective β-adrenergic blocker metoprolol on the release of myocardial proinflammatory cytokines and MMPs. Nishio et al. demonstrated that the actions of epinephrine could be blocked by carvedilol and propanolol, but not by metoprolol, suggesting maintenance of epinephrine effects over β2-adrenergic receptor stimulation [114]. Besides antioxidative properties [115], carvedilol has also been proven to inhibit the generation of free oxygen radicals by neutrophils [116] and to reduce the production of oxidized low density lipoproteins [117]. This might partially explain its expanded effects on the MMP/TIMP-system which could explain the improved cardiac function.

Conclusion

The myocardial ECM is a complex network which balance determines the structural integrity of the heart. Alteration in the matrix degradation system caused by inflammatory mediators, oxygen species and neurohumoral reaction leads to an impairment of left ventricular function as seen in myocarditis and inflammatory cardiomyopathy. The imbalance of the matrix degrading system with induced expression of MMPs and plasminogen activators as well as the reduced expression of TIMPs, leads to a pathologic collagen turnover, with the loss of structural integrity of the heart and an impairment of LV function. Therefore, the regulation of the MMP/TIMP system is an important therapeutic target in the prevention of the progression of inflammatory heart failure. Further investigations are needed to determine the best target for intervention in order to influence this complex system leading to a dynamic balance between collagen accumulation and degradation.

Acknowledgement

This research was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG Transregio 19).

References

[1]
Li
J.
Schwimmbeck
P.L.
Tschope
C.
Leschka
S.
Husmann
L.
Rutschow
S.
et al
Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction
Cardiovasc Res
 
2002
56
235
247
[2]
Kuhl
U.
Pauschinger
M.
Noutsias
M.
Bock
T.
Lassner
D.
Poller
W.
et al
High prevalence of viral genomes and multiple viral infections in the myocardium of adults with “idiopathic” left ventricular dysfunction
Circulation
 
2005
111
887
893
[3]
Pauschinger
M.
Bowles
N.E.
Fuentes-Garcia
F.J.
Pham
V.
Kuhl
U.
Schwimmbeck
P.L.
et al
Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction
Circulation
 
1999
1348
1354
[4]
Kuhl
U.
Pauschinger
M.
Bock
T.
Klingel
K.
Schwimmbeck
C.P.
Seeberg
B.
et al
Parvovirus B19 infection mimicking acute myocardial infarction
Circulation
 
2003
108
945
950
[5]
Noutsias
M.
Seeberg
B.
Schultheiss
H.P.
Kuhl
U.
Expression of cell adhesion molecules in dilated cardiomyopathy: evidence for endothelial activation in inflammatory cardiomyopathy
Circulation
 
1999
99
2124
2131
[6]
D'Armiento
J.
Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction
Trends Cardiovasc Med
 
2002
12
97
101
[7]
Thomas
C.V.
Coker
M.L.
Zellner
J.L.
Handy
J.R.
Crumbley
A.J.
3rd
Spinale
F.G.
Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with endstage dilated cardiomyopathy
Circulation
 
1998
97
1708
1715
[8]
Pauschinger
M.
Knopf
D.
Petschauer
S.
Doerner
A.
Poller
W.
Schwimmbeck
P.L.
et al
Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio
Circulation
 
1999
99
2750
2756
[9]
Torre-Amione
G.
Kapadia
S.
Lee
J.
Durand
J.B.
Bies
R.D.
Young
J.B.
et al
Tumor necrosis factor-α and tumor necrosis factor receptors in the failing human heart
Circulation
 
1996
93
704
[10]
Torre-Amione
G.
Kapadia
S.
Lee
J.
et al
Expression and functional significance of tumor necrosis factor receptors in human myocardium
Circulation
 
1995
92
1487
1493
[11]
Muegge
K.
Williams
T.M.
Kant
J.
Karin
M.
Chiu
R.
Schmidt
A.
et al
Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1
Science
 
1989
246
249
251
[12]
Siwik
D.A.
Chang
D.L.
Colucci
W.S.
Interleukin-1 β and tumor necrosis factor-α decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro
Circ Res
 
2000
86
1259
1265
[13]
Deswal
A.
Petersen
N.J.
Feldman
A.M.
White
B.G.
Mann
D.L.
Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST)
Circulation
 
2001
103
2055
2059
[14]
Mauviel
A.
Cytokine regulation of metalloproteinase gene expression
J Cell Biochem
 
1993
53
288
295
[Review]
[15]
Nagase
H.
Activation mechanisms of matrix metalloproteinases
Biol Chem
 
1997
378
151
160
[16]
Torre-Amione
G.
Kapadia
S.
Benedict
C.
Oral
H.
Young
J.B.
Mann
D.L.
Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunctions (SOLVD)
J Am Coll Cardiol
 
1996
27/5
1201
1206
[17]
Matsumori
A.
Cytokines in myocarditis and cardiomyopathies
Curr Opin Cardiol
 
1996
11
302
309
[18]
Ikonomidis
I.
Andreotti
F.
Economou
E.
Stefanadis
C.
Toutouzas
P.
Nihoyannopoulos
P.
Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin
Circulation
 
1999
100
793
798
[19]
Ridker
P.M.
Rifai
N.
Pfeffer
M.
Sacks
F.
Lepage
S.
Braunwald
E.
Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction
Circulation
 
2000
101
2149
2153
[20]
Sivasubramanian
N.
Coker
M.L.
Kurrelmeyer
K.M.
MacLellan
W.R.
DeMayo
F.J.
Spinale
F.G.
et al
Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor
Circulation
 
2001
104
826
831
[21]
von Haehling
S.
Jankowska
E.A.
Anker
S.D.
Tumour necrosis factor-α and the failing heart: pathophysiology and therapeutic implications
Basic Res Cardiol
 
2004
99
18
28
[22]
Lane
J.R.
Neumann
D.A.
Lafond-Walker
A.
Herskowitz
A.
Rose
N.R.
Role of IL-1 and tumor necrosis factor in coxsackie virus-induced autoimmune myocarditis
J Immunol
 
1993
151
1682
1690
[23]
Liu
L.
Zhao
S.P.
The changes of circulating tumor necrosis factor levels in patients with congestive heart failure influenced by therapy
Int J Cardiol
 
1999
69
77
82
[24]
Liao
F.
Andalibi
A.
Qiao
J.H.
Allayee
H.
Fogelman
A.M.
Lusis
A.J.
Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice
J Clin Invest
 
1994
94
877
884
[25]
Barnes
P.J.
Karin
M.
Nuclear factorκB: a pivotal transcription factor in chronic inflammatory diseases
N Engl J Med
 
1997
336
1066
1071
[26]
Murray
D.R.
Prabhu
S.D.
Chandrasekar
B.
Chronic β-adrenergic stimulation induces myocardial proinflammatory cytokine expression
Circulation
 
2000
101
2338
2341
[27]
Boluyt
M.O.
Long
X.
Eschenhagen
T.
Mende
U.
Schmitz
W.
Crow
M.T.
et al
Isoproterenol infusion induces alterations in expression of hypertrophy-associated genes in rat heart
Am J Physiol
 
1995
269
H638
H647
[28]
Chappel
C.I.
Rona
G.
Balazs
T.
Gaudry
R.
Severe myocardial necrosis produced by isoproterenol in the rat
Arch Int Pharmacodyn Ther
 
1959
122
123
128
[29]
Pauschinger
M.
Rutschow
S.
Chandrasekharan
K.
Westermann
D.
Weitz
A.
Peter Schwimmbeck
L.
et al
Carvedilol improves left ventricular function in murine Coxsackievirus-induced acute myocarditis association with reduced myocardial interleukin-1β and MMP-8 expression and a modulated immune response
Eur J Heart Fail
 
2005
7
444
452
[30]
Richardson
P.
McKenna
W.
Bristow
M.
Report of the 1995 World Health Organisation/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies
Circulation
 
1996
93
341
342
[31]
O'Connell
J.B.
Diagnosis and medical treatment of inflammatory cardiomyopathy
Topol
E.J.
Textbook of Cardiovascular Medicine
1998
Philadelphia
Lippincott-Raven
2309
2336
[32]
Pauschinger
M.
Doerner
A.
Kuehl
U.
Schwimmbeck
P.L.
Poller
W.
Kandolf
R.
et al
Enteroviral RNA replication in the myocardium of patients with left ventricular dysfunction and clinically suspected myocarditis
Circulation
 
1999
889
895
[33]
Kawai
C.
From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death. Learning from the past to the future
Circulation
 
1999
96
3549
3554
[34]
Shioi
T.
Matsumori
A.
Sasayama
S.
Persistent expression of cytokine in the chronic stage of viral myocarditis in mice
Circulation
 
1996
94
2930
2937
[35]
Matsumori
A.
Molecular and immune mechanisms in the pathogenesis of cardiomyopathy: role of viruses, cytokines and nitric oxide
Jpn Circ J
 
1997
61
275
291
[36]
Rose
N.R.
Hill
S.L.
The pathogenesis of postinfectious myocarditis
Clin Immunol Immunopathol
 
1996
80
92
99
[37]
Wilson
F.M.
Miranda
Q.R.
Chason
J.L.
Lerner
M.
Residual pathologic changes following murine coxsackie A and B myocarditis
Am J Pathol
 
1969
55
253
265
[38]
Seko
Y.
Shinkai
Y.
Kawasaki
A.
Yagita
H.
Okumura
K.
Takaku
F.
et al
Expression of perforin in infiltrating cells in murine hearts with acute myocarditis caused by coxsackievirus B3
Circulation
 
1991
84
788
795
[39]
Feldman
A.M.
McNamara
D.
Myocarditis
N Engl J Med
 
2000
343
1388
1398
[40]
Chow
L.H.
Beisel
K.W.
McManus
B.M.
Enteroviral infection of mice with severe combined immunodeficiency. evidence for direct viral pathogenesis of myocardial injury
Lab Invest
 
1992
66
24
31
[41]
Herzum
M.
Ruppert
V.
Kuytz
B.
Jomaa
H.
Nakamura
I.
Maisch
B.
Coxsackievirus B3 infection leads to cell death of cardiac myocytes
J Mol Cell Cardiol
 
1994
26
907
913
[42]
McManus
B.M.
Chow
L.H.
Wilson
J.E.
Anderson
D.R.
Gulizia
J.M.
Gauntt
C.J.
et al
Direct myocardial injury by enterovirus: a central role in the evolution of murine myocarditis
Clin Immunol Immunopathol
 
1993
68
159
169
[43]
Badorff
C.
Lee
G.H.
Lamphear
B.J.
Martone
M.E.
Campbell
K.P.
Rhoads
R.E.
et al
Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy
Nat Med
 
1999
5
320
326
[44]
Seko
Y.
Shinkai
Y.
Kawasaki
A.
Yagita
H.
Okumura
K.
Yazaki
Y.
Evidence of perforin-mediated cardiac myocyte injury in acute murine myocarditis caused by coxsackie virus B3
J Pathol
 
1993
170
53
58
[45]
Godeny
E.K.
Gauntt
C.J.
Involvement of natural killer cells in coxsackievirus B3 viral-induced myocarditis
J Immunol
 
1986
137
1695
1702
[46]
Godeny
E.K.
Gauntt
C.J.
Murine natural killer cells limit coxsackie virus B3 replication
J Immunol
 
1987
139
913
918
[47]
Seko
Y.
Takahashi
N.
Yagita
H.
Okumura
K.
Yazaki
Y.
Expression of cytokine mRNAs in murine hearts with acute myocarditis caused by Coxsackievirus B3
J Pathol
 
1997
183
105
108
[48]
Mason
J.W.
O'Connell
J.B.
Herskowitz
A.
Rose
N.R.
McManus
B.M.
Billingham
M.E.
et al
A clinical trial of immunosuppressive therapy for myocarditis. The myocarditis treatment trial investigators
N Engl J Med
 
1995
333
269
275
[49]
McCarthy
R.E.
3rd
Boehmer
J.P.
Hruban
R.H.
Hutchins
G.M.
Kasper
E.K.
Hare
J.M.
et al
Long-term outcome of fulminant myocarditis as compared with (nonfulminat) myocarditis
N Engl J Med
 
2000
85
499
504
[50]
Herzum
M.
Weller
R.
Jomaa
H.
Wietrzychowski
F.
Pankuweit
S.
Mahr
P.
et al
Left ventricular hemodynamic parameters in the course of acute experimental coxsackievirus B 3 myocarditis
J Mol Cell Cardiol
 
1995
27
1573
1580
[51]
Kyu
B.
Matsumori
A.
Sato
Y.
Okada
I.
Chapman
N.M.
Tracy
S.
Cardiac persistence of cardioviral RNA detected by polymerase chain reaction in a murine model of dilated cardiomyopathy
Circulation
 
1992
86
522
530
[52]
Klingel
K.
Hohenadl
C.
Canu
A.
Albrecht
M.
Seemann
M.
Mall
G.
et al
Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation
Proc Natl Acad Sci U S A
 
1992
89
314
318
[53]
Lenzo
J.C.
Fairweather
D.
Cull
V.
Shellam
G.R.
Lawson
C.M.
Characterisation of murine cytomegalovirus myocarditis: cellular infiltration of the heart and virus persistence
J Mol Cell Cardiol
 
2002
34
629
640
[54]
Wessely
R.
Klingel
K.
Santana
L.F.
Dalton
N.
Hongo
M.
Jonathan Lederer
W.
et al
Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy
J Clin Invest
 
1998
102
1444
1453
[55]
Fakhouri
F.
Placier
S.
Ardaillou
R.
Dussaule
J.C.
Chatziantoniou
C.
Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-β
J Am Soc Nephrol
 
2001
12
2701
2710
[56]
Smits
J.F.M.
van Krimpen
C.
Schoemaker
R.G.
Cleutjens
J.P.
Daemen
M.J.
Angiotensin II receptor blockade after myocardial infarction in rats: effects on hemodynamics, myocardial DNA synthesis, and interstitial collagen content
J Cardiovasc Pharmacol
 
1992
20
772
778
[57]
Li
Y.Y.
McTiernan
C.F.
Feldman
A.M.
Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells
Cardiovasc Res
 
1999
42
162
172
[58]
Weber
K.T.
Anversa
P.
Armstrong
P.W.
Brilla
C.G.
Burnett
J.C.
Jr.
Cruickshank
J.M.
et al
Remodeling and reparation of the cardiovascular system
J Am Coll Cardiol
 
1992
30
3
16
[59]
Woessner
J.F.
Jr.
Nagase
H.
Introduction to the matrix metalloproteinases (MMPs). Matrix Metalloproteinases and TIMPs
2000
New York
Oxford University Press
1
10
[60]
Woessner
J.F.
Jr.
The matrix metalloproteinase family
Parks
W.C.
Mecham
R.P.
Matrix Metalloproteinases
1998
San Diego, Calif
Academic Press
1
14
[61]
Jeffrey
J.J.
Interstitial collagenases
Parks
W.C.
Mecham
P.
Matrix Metalloproteinases
1998
San Diego
Academic Press
15
42
[62]
Coker
M.L.
Thomas
C.V.
Clari
M.J.
Hendrick
J.W.
Krombach
R.S.
Galis
Z.S.
et al
Myocardial matrix metalloproteinase activity and abundance with congestive heart failure
Am J Physiol
 
1998
274
H1516
H1523
[63]
Coker
M.L.
Doscher
M.A.
Thomas
C.V.
Galis
Z.S.
Spinale
F.G.
Matrix metalloproteinase activity and expression in isolated LV myocyte preparations
Am J Physiol
 
1999
277
H777
H787
[64]
Nagaoka
I.
Hirota
S.
Increased expression of matrix metalloproteinase-9 in neutrophils in glycogen-induced peritoneal inflammation of guinea pigs
Inflamm Res
 
2000
49
55
62
[65]
Tao
Z.Y.
Cavasin
M.A.
Yang
F.
Liu
Y.H.
Yang
X.P.
Temporal changes in matrix metalloproteinase expression and inflammatory response associated with cardiac rupture after myocardial infarction in mice
Life Sci
 
2004
74
1561
1572
[66]
Miyamori
H.
Takino
T.
Seiki
M.
Sato
H.
Human membrane type-2 matrix metalloproteinase is defective in cell-associated activation of progelatinase A
Biochem Biophys Res Commun
 
2000
267
796
800
[67]
Maquart
F.X.
Pickart
L.
Laurent
M.
Gillery
P.
Monboisse
J.C.
Borel
J.P.
Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu2+
FEBS Lett
 
1988
238
343
346
[68]
Diekmann
O.
Tschesche
H.
Degradation of kinins, angiotensins and substance P by polymorphonuclear matrix metalloproteinases MMP 8 and MMP 9
Braz J Med Biol Res
 
1994
27
1865
1876
[69]
Fowlkes
J.L.
Enghild
J.J.
Suzuki
K.
Nagase
H.
Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures
J Biol Chem
 
1994
269
25742
25746
[70]
Kridel
S.J.
Chen
E.
Kotra
L.P.
Howard
E.W.
Mobashery
S.
Smith
J.W.
Substrate hydrolysis by matrix metalloproteinase-9
J Biol Chem
 
2001
276
20572
20578
[71]
Egeblad
M.
Werb
Z.
New functions for the matrix metalloproteinases in cancer progression
Nat Rev Cancer
 
2002
2
163
176
[72]
Emonard
H.
Grimaud
J.A.
Matrix metalloproteinases. A review
Cell Mol Biol
 
1990
36
131
153
[73]
Benbow
U.
Brinckerhoff
C.E.
The AP-1 site and MMP gene regulation: What is all the fuss about?
Matrix Biol
 
1997
15
519
526
[74]
Bond
M.
Chase
A.J.
Baker
A.H.
Newby
A.C.
Inhibition of transcription factor NF-κB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells
Cardiovasc Res
 
2001
50
556
565
[75]
Eberhardt
W.
Huwiler
A.
Beck
K.F.
Walpen
S.
Pfeilschifter
J.
Amplification of IL-1β-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of matrix metalloproteinase-9 and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways
J Immunol
 
2000
165
5788
5797
[76]
Hozumi
A.
Nishimura
Y.
Nishiuma
T.
Kotani
Y.
Yokoyama
M.
Induction of MMP-9 in normal human bronchial epithelial cells by TNFα via NF-κB-mediated pathway
Am J Physiol, Lung Cell Mol Physiol
 
2001
281
L1444
L1452
[77]
Futamura
M.
Kamiya
S.
Tsukamoto
M.
Hirano
A.
Monden
Y.
Arakawa
H.
et al
A potent inhibitor of transcription controlled by the Ras responsive element, inhibits Rasmediated transformation activity with suppression of MMP-1 and MMP-9 in NIH3T3 cells
Oncogene
 
2001
20
6724
6730
[78]
Thant
A.A.
Nawa
A.
Kikkawa
F.
Ichigotani
Y.
Zhang
Y.
Sein
T.T.
et al
Fibronectin activates matrix metalloproteinase-9 secretion via the MEK1-MAPK and the PI3K-AKT pathways in ovarian cancer cells
Clin Exp Metastasis
 
2001
18
423
428
[79]
Piacentini
L.
Gray
M.
Honbo
N.Y.
Chentoufi
J.
Bergman
M.
Karliner
J.S.
Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C
J Mol Cell Cardiol
 
2000
32
565
576
[80]
Kupfahl
C.
Pink
D.
Friedrich
K.
Zurbrugg
H.R.
Neuss
M.
Warnecke
C.
et al
Angiotensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart
Cardiovasc Res
 
2000
46
463
475
[81]
Zhou
M.
Zhang
Y.
Ardans
J.A.
Wahl
L.M.
Interferon-γ differentially regulates monocyte matrix metalloproteinase-1 and-9 through tumor necrosis factor-α and caspase 8
J Biol Chem
 
2003
46
45406
45413
[82]
Wahl
S.M.
Allen
J.B.
Weeks
B.S.
Wong
H.L.
Klotman
P.E.
Transforming growth factor β enhances integrin expression and type IV collagenase secretion in human monocytes
Proc Natl Acad Sci U S A
 
1993
90
4577
4581
[83]
Coker
M.L.
Jolly
J.R.
Joffs
C.
Etoh
T.
Holder
J.R.
Bond
B.R.
et al
Matrix metalloproteinase expression and activity in isolated myocytes after neurohormonal stimulation
Am J Physiol, Heart Circ Physiol
 
2001
281
H543
H551
[84]
Reinhardt
D.
Sigusch
H.H.
Hensse
J.
Tyagi
S.C.
Korfer
R.
Figulla
H.R.
Cardiac remodeling in end stage heart failure: Upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP
Heart
 
2002
88
525
530
[85]
Matsutomo
K.
Makino
N.
Fushiki
M.S.
Effects of losartan on the collagen degradative enzymes in hypertrophic and congestive types of cardiomyopathic hamsters
Mol Cell Biochem
 
2001
224
19
27
[86]
Rosano
L.
Varmi
M.
Salani
D.
Di Castro
V.
Spinella
F.
Natali
P.G.
et al
Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells
Cancer Res
 
2001
61
8340
8346
[87]
Tsuruda
T.
Boerrigter
G.
Huntley
B.K.
Noser
J.A.
Cataliotti
A.
Costello-Boerrigter
L.C.
et al
Brain natriuretic peptide is produced in cardiac fibroblasts and induces matrix metalloproteinases
Circ Res
 
2002
91
1127
1134
[88]
He
C.S.
Wilhelm
S.M.
Pentland
A.P.
Marmer
B.L.
Grant
G.A.
Eisen
A.Z.
et al
Tissue cooperation in a proteolytic cascade activating human interstitial collagenase
Proc Natl Acad Sci USA
 
1989
86
2632
2636
[89]
Heymans
S.
Lupu
F.
Terclavers
S.
Vanwetswinkel
B.
Herbert
J.M.
Baker
A.
et al
Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice
Am J Pathol
 
2005
166
15
25
[90]
Saksela
O.
Rifkin
D.B.
Cell-associated plasminogen activation: regulation and physiological functions
Annu Rev Cell Biol
 
1988
4
93
126
[91]
Nerlov
C.
Rorth
P.
Blasi
F.
Johnson
M.
Essential AP-1 and PEA3 binding elements in the human urokinase enhancer display cell type-specific activity
Oncogene
 
1991
6
1583
1592
[92]
Ogura
N.
Tobe
M.
Tamaki
H.
Nagura
H.
Abiko
Y.
Il-1β increases uPA and uPA receptor expression in human gingival fibroblasts
IUBMB
 
2001
51
381
385
[93]
Lijnen
H.R.
Arza
B.
Van Hoef
B.
Collen
D.
Declerck
P.J.
Inactivation of plasminogen activator inhibitor-1 by specific proteolysis with stromelysin-1 (MMP-3)
J Biol Chem
 
2000
275
37645
37650
[94]
Lijnen
H.R.
Van Hoef
B.
Collen
D.
Inactivation of the serpin α (2)-antiplasmin by stromelysin-1
Biochim Biophys Acta
 
2001
1547
206
213
[95]
Spinale
F.G.
Matrix metalloproteinases: regulation and dysregulation in the failing heart
Circ Res
 
2002
90
520
530
[96]
Li
Y.Y.
McTiernan
C.F.
Feldman
A.M.
Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling
Cardiovasc Res
 
2000
46
214
224
[97]
Ries
C.
Petrides
P.E.
Cytokine regulation of matrix metalloproteinase activity and its regulatory dysfunction in disease
Biol Chem
 
1995
376
345
355
[98]
Goldberg
G.I.
Marmer
B.L.
Grant
G.A.
Eisen
A.Z.
Wilhelm
S.
He
C.
Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloprotease designated TIMP
Proc Natl Acad Sci Am
 
1989
86
8207
8211
[99]
Zucker
S.
Lysik
R.M.
Zarrabi
H.M.
Moll
U.
Tickle
S.P.
Stetler-Stevenson
W.
et al
Plasma assay of matrix metalloproteinases (MMPs) and MMPinhibitor complexes in cancer. Potential use in predicting metastasis and monitoring treatment
Ann NY Acad Sci
 
1994
732
248
262
[100]
Amour
A.
Slocombe
P.M.
Webster
A.
Butler
M.
Knight
C.G.
Smith
B.J.
et al
TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3
FEBS Lett
 
1998
435
39
44
[101]
Brew
A.
Dinakarpandian
D.
Nagase
H.
Tissue inhibitors of metalloproteinases: evolution, structure and function1
Biochim Biophys Acta
 
2000
1477
267
283
[102]
Nagase
H.
Itoh
Y.
Binner
S.
Interaction of α2-Macroglobulin with matrix metalloproteinases and its use for identification of their active forms
Annals Natl Acad Sci
 
1994
732
294
302
[103]
Moutsiakis
D.
Mancuso
P.
Krutzsch
H.
Stetler-Stevenson
W.
Zucker
S.
Characterization of metalloproteinases and tissue inhibitors of metallopteinases in human plasma
Connect Tissue Res
 
1992
28
213
230
[104]
Woodiwiss
A.J.
Tsotetsi
O.J.
Sprott
S.
Lancaster
E.J.
Mela
T.
Chung
E.S.
et al
Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction
Circulation
 
2001
103
155
160
[105]
Okada
Y.
Naka
K.
Kawamura
K.
Matsumoto
T.
Nakanishi
I.
Fujimoto
N.
et al
Localization of matrix metalloproteinase 9 (92 kilodalton gelatinase/type IV collagenase=gelatinase B) in osteoclasts: implications for bone resorption
Lab Invest
 
1995
72
311
322
[106]
Ducharme
A.
Frantz
S.
Aikawa
M.
Rabkin
E.
Lindsey
M.
Rohde
L.E.
et al
Targeted deletion of matrix metalloproteinase 9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction
J Clin Invest
 
2000
106
55
62
[107]
Pauschinger
M.
Hoppe
K.
Schwimmbeck
P.L.
Relevance of myocardial inflammation for the activation of matrix metalloproteinase expression in patients with inflammatory cardiomyopathy
Circulation
 
2003
108
IV-24
[108]
Schwartzkopff
B.
Fassbach
M.
Pelzer
B.
Brehm
M.
Strauer
B.E.
Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy
Eur J Heart Fail
 
2002
4
439
444
[109]
McCormick
R.J.
Thomas
D.
Collagen crosslinking in the heart: relationship to development and function
Basic Appl Myol
 
1998
8
143
150
[110]
Gunja Smith
Z.
Morales
A.R.
Romanelli
R.
Woessner.
J.F.
Jr.
Remodelling of human myocardial collagen in idiopathic dilated hypertrophy
Am J Pathol
 
1996
148
1639
1648
[111]
Klappacher
G.
Franzen
P.
Haab
D.
Mehrabi
M.
Binder
M.
Plesch
K.
et al
Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopathy and impact on dignosis and prognosis
Am J Cardiol
 
1995
75
913
918
[112]
Kuhl
U.
Pauschinger
M.
Schwimmbeck
P.L.
Seeberg
B.
Lober
C.
Noutsias
M.
et al
Interferon- β treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction
Circulation
 
2003
107
2793
2798
[113]
Tschope
C.
Westermann
D.
Steendijk
P.
Noutsias
M.
Rutschow
S.
Weitz
A.
et al
Hemodynamic characterization of left ventricular function in experimental coxsackieviral myocarditis: effects of carvedilol and metoprolol
Eur J Pharmacol
 
2004
491
173
179
[114]
Nishio
R.
Shioi
T.
Sasayama
S.
Matsumori
A.
Carvedilol increases the production of interleukin-12 and interferon-γ and improves the survival of mice infected with the encephalomyocarditis virus
JACC
 
2003
41
340
345
[115]
López
B.L.
Christopher
T.A.
Yue
T.L.
Ruffolo
R.
Fenerstein
G.Z.
Ma
X.L.
Carvedilol, a new β-adrenoreceptor blocker antihypertensive drug, protects against free-radical induced endothelial dysfunction
Pharmacology
 
1995
51
165
173
[116]
Yue
T.L.
McKenna
P.J.
Gu
J.L.
Cheng
H.Y.
Ruffolo
R.R.
Jr.
Feuerstein
G.Z.
Carvedilol, a new vasodilating adrenoceptor blocker antihypertensive drug, protects endothelial cells from damage initiated by xanthine–xanthine oxidase and neutrophils
Cardiovasc Res
 
1994
28
400
406
[117]
Yue
T.L.
McKenna
P.J.
Lysko
P.G.
Ruffolo
R.R.
Jr.
Feuerstein
G.Z.
Carvedilol, a new antihypertensive, prevents oxidation of human low density lipoprotein by macrophages and copper
Atherosclerosis
 
1992
97
209
213

Author notes

Time for primary review 22 days