This induction can be direct, through the degradation of pathogens within phagolysosomes, or indirect, through the activation of key pattern recognition receptors PRRs , such as toll-like receptors TLRs. Unfortunately, excess production of proteases leads to maladaptive host responses and excess tissue inflammation and damage.
Proteases also offer a valuable target in many therapeutic settings, including Alzheimer's, cancer, and viral infection. MMP-9 , a matrix metallopeptidase, plays a role in angiogenesis and is a therapeutic target for cancer. Because of their significance in the pathology of disease, proteases are a relevant drug target class. Reagents Search. Google Search. Enzymes Proteases Kinases. The increase of cardiac cell-infiltration and release of inflammatory cytokines directly correlate to the development of left ventricular dysfunction . 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  and in the development of left ventricular dilatation in mice with persistence of Coxsackievirus B3 . 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 .
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. 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. 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 AT 1 -receptor antagonism .
Fibrillar collagen turnover results from the equilibrium between the synthesis and the degradation of collagen, mainly types I and III. 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 . 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.
Collagen degradation is an important step in ECM remodeling, mainly due to matrix metalloproteinases MMPs and serine-proteinases.
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The matrix metalloproteinases are a family of 20 different species of zinc-dependent enzymes  , 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].
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In addition, these substrate specificities and functions classify the secreted MMPs in three different groups. 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.
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]. 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 .
Beside the ECM components, the target substrates of the MMPs also include nonmatrix proteins such as cytokines, receptors and adhesions molecules [68—70].
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This explains additional functions of MMPs as for example regulating growth, cell pathways, and angiogenesis . Simplified mechanism of regulation in the Matrix-Degradation-System. Importance of inflammatory mediators. The synthesis of MMPs at the transcriptional level is influenced by multiple cytokines, neurohormones and growth factors . Different signaling pathways have been shown to be involved in regulation of the expression of MMPs [73—80]. 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 in neonatal rat fibroblast . 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].
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Furthermore, natriuretic peptides like BNP brain natriuretic peptide are able to induce the MMP-synthesis in chronic heart failure and myocardial remodeling . 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 .
Furthermore they can bind latent MMPs at the aminoterminus thereby preventing their activation . Some differences in the inhibitory properties of the different TIMPs have been reported. 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. This widespread influence of inflammatory reaction on the regulation of the matrix degradation system reflects a deregulation in disease with pathologically elevated inflammatory mediators.
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 . 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. MMP-9, which depolimerizes the cross-linked polymers of collagen type I  , seems to play an important role.
Furthermore, LV enlargement after myocardial infarction could be prevented by deletion of the MMP-9 gene . 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. As described above, a restored interstitial matrix with an undilated chamber could be demonstrated in a uPA knock-out model of chronic volume overload  , 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.
Dominance of matrix degrading components with loss of their controlling agents. 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  in dilated cardiomyopathy without inflammation.
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This is in line with the results of Schwartzkopff et al. 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 .
Proteolytic Enzymes: How They Work, Benefits and Sources
This was also verified by Pauschinger et al. McCormick et al. 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 . 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 .
In this study the viral elimination led to significantly reduced inflammation, which furthermore reflects the pivotal role of viral persistence and chronic induced inflammation.