Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis

Cheung, Caroline; Luo, Honglin; Yanagawa, Bobby; Leong, Hon S.; Samarasekera, Dinesh; Lai, John Chi Keung; Suarez, Agripina; Zhang, Jingchun; McManus, Bruce M.

doi:10.1016/j.carpath.2005.11.008

Cited by 52 publications

(51 citation statements)

References 46 publications

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“…These findings differ from a recent study that reported that TIMP-1 protein levels were readily detected in the uninfected myocardium and remained unaltered by CVB3 infection. 21 The reason for this discrepancy is unknown, but we considered it particularly important to verify that the changes that we observed in TIMP-1 mRNA after infection were reflected in the levels of TIMP-1 protein. To this end, an ELISA assay was performed on protein extracts from heart tissues of uninfected mice and of mice infected with CVB3 3 or 7 days previously.…”

Section: Myocardial Timp-1 Expression Is Up-regulated During Cvb3 Infmentioning

confidence: 90%

“…Increased expression and activation of metalloproteinases during CVB3 infection have been implicated in myocardial injury, 13,21,[32][33][34][35] and a recent study described increased activity of both MMP-2 and MMP-9 in heart tissues during CVB3-induced myocarditis. 35 Because the primary biological function of TIMP-1 is thought to be its role as an endogenous MMP inhibitor, we determined whether TIMP-1 deficiency affected CVB3-induced MMP activity in the heart.…”

Section: Diminished Mmp Activity In the Hearts Of Cvb3-infected Timp-mentioning

confidence: 99%

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Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Crocker

Frausto

Whitmire

et al. 2007

The American Journal of Pathology

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Coxsackievirus B3 (CVB3) is a major cause of acute myocarditis, a serious condition that is refractory to treatment. Myocardial damage results in tissue remodeling that, if too extensive, may contribute to disease. Remodeling is achieved by extracellular proteolysis mediated by the matrix metalloproteinases (MMPs), and MMP activity is counterbalanced by tissue inhibitors of MMPs (TIMPs). We show herein that TIMP-1 expression is induced in the myocardium by CVB3 infection. Surprisingly, TIMP-1 knockout mice exhibited a profound attenuation of myocarditis, with increased survival. The amelioration of disease in TIMP-1 knockout mice was not attributable to either an altered T-cell response to the virus or to reduced viral replication. These data led us to propose a novel function for TIMP-1: its highly localized upregulation might arrest the MMP-dependent migration of inflammatory cells at sites of infection, thereby anatomically focusing the adaptive immune response. The benefits of TIMP-1 blockade in treating viral myocarditis were confirmed by administering, to wild-type animals, TIMP-1-specific siRNA or polyclonal antisera, both of which diminished CVB3-induced myocarditis. These unexpected findings indicate that increased TIMP-1 expression exacerbates, rather than ameliorates, CVB3-induced myocarditis and, thus, that TIMP-1 may represent a target for the treatment of virus-induced heart disease. (Am J Pathol

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Section: Myocardial Timp-1 Expression Is Up-regulated During Cvb3 Infmentioning

confidence: 90%

Section: Diminished Mmp Activity In the Hearts Of Cvb3-infected Timp-mentioning

confidence: 99%

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Crocker

Frausto

Whitmire

et al. 2007

The American Journal of Pathology

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“…These enzymes have previously been shown to be involved in acute myocarditis and may play a role in long-term remodeling. 26 We found that neither expression of MMP-2 nor MMP-9 transcripts were significantly altered between the two groups, as shown in Figure 5. MMP-2 transcript was present abundantly in all samples, whereas MMP-9 was produced minimally in both groups.…”

Section: Protease Expressionmentioning

confidence: 74%

“…Our laboratory has previously shown that the gelatinases, MMP-2 and MMP-9, as well as the metalloelastase MMP-12 were increased during acute myocarditis and remained upregulated at 30 days pi. 26 We hypothesized that these proteases play a role in regulating the immune response by modulating the activity and expression of cytokines, and also in matrix remodeling. In this study, we found that MMP-2 and MMP-12 remained increased at 10 weeks pi in both groups while MMP-9, which we previously found to be predominantly secreted by immune cells, had returned to basal levels.…”

Section: Discussionmentioning

confidence: 99%

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Neutralizing anti-4-1BBL treatment improves cardiac function in viral myocarditis

Cheung

Deisher

Luo

et al. 2007

Laboratory Investigation

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Coxsackievirus B3 (CVB3) is the most common causative agent of infectious myocarditis. Chronic inflammation, loss of contractile tissue, and maladaptive remodeling all contribute to dilated cardiomyopathy and heart failure. The 4-1BB receptor is a costimulatory molecule expressed by T cells and cardiomyocytes. We infected mice with CVB3 to examine if virus infection triggers 4-1BB activation and whether inhibition of this pathway will reduce inflammation and improve heart function. Echocardiography was performed on days 3, 9, 30 and at 10 weeks post-infection (pi) and ejection fraction (EF), left ventricular (LV) wall thickness, contractility, and internal cardiac dimensions were measured. At day 9, reduced rate of wall thickening (30717 vs 70719%), increased LV wall thickness (0.1570.04 vs 0.0970.01 cm in diastole and 0.1970.04 vs 0.1570.02 cm in systole), and reduced cardiac volume (0.01370.004 vs 0.02370.003 ml in diastole and 0.00470.002 ml vs 0.00770.001 ml in systole) were observed in infected hearts as compared with shams. At 14 days pi, CVB3-infected mice were randomly assigned to receive either anti-4-1BBL neutralizing (M522) or control antibodies (Ab) for 8 weeks. Cardiac damage, fibrosis, and inflammation were assessed by histological stains and immunohistochemistry. Polymerase chain reaction (PCR) was utilized to detect matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12 expressions. At 10 weeks pi, M522 treatment improved LV wall thickening rate (À10713 vs À49716%, expressed as percentage change from baseline) and reduced diastolic LV posterior wall thickness (17710 vs 57747%, expressed as percentage change from baseline), cardiac damage as assessed by histological scores (0 vs 1.371.5), fibrosis by collagen volume fraction (3.270.6 vs 4.972.2%), overall inflammation (5.971.3 vs 8.574.1%), and T-cell infiltration (1.370.9 vs 4.373.8%) as compared to control. MMP-12 was highly increased during acute and chronic myocarditis, but was significantly decreased by M522 treatment. Thus, long-term inhibition of the 4-1BB pathway reduces cardiac damage, remodeling, and inflammation during viral myocarditis.

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Extracellular Matrix Communication and Turnover in Cardiac Physiology and Pathology

Takawale

Sakamuri

Kassiri

2015

Comprehensive Physiology

100

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Despite significant advances in treating heart disease, heart failure remains a major cause of morbidity and mortality. Regardless of the initiating cause(s), heart failure is associated with disruptions in the myocardial extracellular matrix (ECM). ECM is a dynamic structure and its physiological turnover is mediated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Research in the past two decades has revealed that the function of ECM extends beyond its role in providing structural support. Similarly, ECM regulatory proteins, MMPs and TIMPs, have been demonstrated to play diverse and ECM-independent roles in tissue remodeling and homeostasis. ECM is a network structure that in addition to providing structural support, serves as an extracellular reservoir for a number of growth factors and cytokines, and plays a central role in interstitial transport of different molecules (hormones, growth factors, drugs, etc.). This is mainly through the action of nonstructural ECM components, proteoglycans and matricellular proteins, which are also critical in cell-ECM interactions and overall ECM remodeling. As such, sustaining the ECM integrity is not only critical in preserving cardiac geometry and function, it is essential in ensuring optimal delivery of different molecules to their site of action. Further, ECM composition and integrity in disease should be considered in designing drugs with a specific site of action. In this review article, we provide an overview of the ECM structure, components, its function in interstitial transport, heart disease-dependent ECM remodeling, and the potential therapeutic approaches in preserving the diseased myocardial ECM and cardiac function.

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Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis

Cited by 52 publications

References 46 publications

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Neutralizing anti-4-1BBL treatment improves cardiac function in viral myocarditis

Extracellular Matrix Communication and Turnover in Cardiac Physiology and Pathology

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