Myocardial Remodeling in Viral Heart Disease: Possible Interactions Between Inflammatory Mediators and MMP-TIMP System

Pauschinger, Matthias; Chandrasekharan, Kumaran; Schultheiss, Heinz‐Peter

doi:10.1023/b:hrev.0000011391.81676.3c

Cited by 50 publications

(34 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22 Conversely, adenovirus-mediated expression of TIMP-1 was reported to mitigate the severity of ischemic injury. 39 These data suggested that TIMP-1 might exert a protective effect in the myocardium, consistent with the concept that increased MMP activity is a key process driving myocardial pathology after myocardial infarction or stress-related injuries 13,32 ; by this reasoning, expression of TIMP-1 is a physiological response that counterbalances MMP proteolysis, 14,40,41 and TIMP-1 blockade should, in theory, exacerbate disease. We show here that TIMP-1 expression in the heart increases during viral myocarditis, consistent with many studies that show that TIMP-1 is up-regulated in response to myocardial injury.…”

Section: Discussionsupporting

confidence: 68%

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

View full text Add to dashboard Cite

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

show abstract

Section: Discussionsupporting

confidence: 68%

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

View full text Add to dashboard Cite

show abstract

“…22 In addition to their role in modulating lymphocyte function, these proinflammatory cytokines also disturb the balance between MMPs and TIMPs, which results in overall increased MMP activity. 11 Reduced cytokine expression in the absence of uPA may also have resulted from a reduced number of inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

“…Inactivation of the uPA gene impaired wound healing after acute myocardial infarction 6 and prevented pressure overload-induced cardiac failure, 7 whereas absence of MMP-2 or MMP-9 prevented cardiac rupture 6,8 and dilatation 9 after myocardial infarction. A single study showed increased transcript levels of MMP-9 together with decreased transcript levels of tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-4 during CVB3-induced myocarditis 10 (reviewed in Pauschinger et al 11 ). Given the possible importance of the cardiac matrix in myocarditis, the present study aimed to investigate whether increased expression of the proteolytic enzymes uPA and MMPs may mediate acute inflammation and cardiac dilatation during CVB3-induced viral myocarditis.…”

Section: Clinical Perspective P 573mentioning

confidence: 96%

“…To investigate whether absence of uPA and associated reduction in inflammation and MMP activity may alter cytokine expression, 11 transcript levels of IL-6, Il-1␤, and TGF-␤ were determined in cardiac extracts of CVB3-or sham-infected hearts at 7 days. Absence of uPA decreased the transcript levels of proinflammatory cytokines, including IL-6 by 47%, IL-1␤ by 55% (PϽ0.05 for both), and TGF-␤ by 13% (Pϭ0.08) compared with WT levels at 7 days after CVB3 infection, whereas transcript levels were very low and did not differ significantly in sham-treated uPA knockout hearts compared with WT hearts (data not shown).…”

Section: Reduced Cytokine Expression In Absence Of Upamentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral Myocarditis

et al. 2006

Self Cite

View full text Add to dashboard Cite

Background-Acute viral myocarditis is an important cause of cardiac failure in young adults for which there is no effective treatment apart from general heart failure therapy. The present study tested the hypothesis that increased expression of the proteinases urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) is implicated in cardiac inflammation, injury, and subsequent failure during Coxsackievirus-B3 (CVB3)-induced myocarditis. Methods and Results-First, we showed increased expression and activity of uPA and MMP-9 in wild-type mice at 7 days of CVB3-induced myocarditis. Targeted deletion of uPA, which resulted in reduced MMP activity and cytokine expression or inhibition of MMPs by adenoviral gene overexpression of tissue inhibitor of metalloproteinases-1, decreased cardiac inflammation and reduced myocardial necrosis at 7 days and decreased cardiac fibrosis at 35 days after CVB3 infection. Importantly, loss of uPA or MMP activity prevented CVB3-induced cardiac dilatation and dysfunction, as determined by serial echocardiography. Conclusions-Loss

show abstract

“…33 It has been shown that leukocytes express high levels of TIMPs, 32 and a decrease in TIMP expression can yield a net increase in MMP activity. 34 Therefore, it was determined whether low levels of H 2 O 2 such as those generated by VCAM-1 signaling could modulate MMP and TIMP expression in the resting splenic lymphocytes. Lymphocytes were incubated in the presence of 1 M H 2 O 2 for 0, 0.25, or 5 hours.…”

Section: Lymphocyte Mmp-9 Activation Is Blocked By Inhibition Of Endomentioning

confidence: 99%

Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species

Deem

Cook‐Mills

2004

Blood

171

209

View full text Add to dashboard Cite

Lymphocytes bound at endothelial cell junctions extravasate within minutes. Lymphocyte-endothelial cell binding is mediated by receptors such as vascular cell adhesion molecule 1 (VCAM-1). VCAM-1 activates endothelial cell nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in minutes, and this activity is required for VCAM-1-dependent lymphocyte migration. In this report, we examined mechanisms for activation of matrix metalloproteinases (MMPs) during VCAM-1-dependent lymphocyte migration. Lymphocyte binding to VCAM-1 rapidly activated endothelial cell-associ- IntroductionLymphocytes migrate out of the blood between endothelial cells and into tissues where the lymphocytes can interact with antigen. Endothelial cells bind lymphocytes through cell surface adhesion molecules. One of these adhesion molecules is vascular cell adhesion molecule 1 (VCAM-1). It is important to understand VCAM-1 signaling because it is involved in several diseases. For example, VCAM-1 is required for eosinophil infiltration into the lung in experimental ovalbumin-induced asthma, 1 as well as T-cell infiltration across the blood-brain barrier in experimental allergic encephalomyelitis (EAE). 2 In addition, VCAM-1 functions in combination with other adhesion molecules during chronic inflammation and tumor metastasis. Understanding VCAM-1 signaling may have important implications for disease intervention.We have reported that VCAM-1 signaling in endothelial cells is required for VCAM-1-dependent lymphocyte migration. 3 Stimulation of VCAM-1 activates endothelial cell nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which catalyzes the release of low levels of reactive oxygen species (ROS) in cytokinetreated human umbilical vein endothelial cells (HUVECs) and in endothelial cell lines. 4,5 These ROS are required for VCAM-1-stimulated endothelial cell actin restructuring and lymphocyte migration. 3,6,7 Therefore, ROS are involved in modulating endothelial cell function to promote VCAM-1-dependent lymphocyte migration.It has been reported that VCAM-1-dependent adhesion of a T-cell line activates lymphocyte matrix metalloproteinases (MMPs) after 5 hours. 8 However, the mechanism(s) for VCAM-1 activation of lymphocyte MMPs is not known. It is also not known whether VCAM-1 signaling activates endothelial cell MMPs. Activated MMPs degrade extracellular matrix, cell surface receptors in cell-cell junctions, and tight junction proteins. 9-11 MMP activation can be regulated by ROS. In smooth muscle cells, the latent form of MMP-2 (pro-MMP-2) is released after mechanical stretchstimulated production of ROS by NADPH oxidase. 12 In cell-free systems, low concentrations of ROS can activate pro-MMPs by oxidation of the sulfide bond in the prodomain of the MMP followed by release of this prodomain by autocatalytic cleavage. 13 In this report, we demonstrate that VCAM-1 rapidly activates endothelial cell-associated MMPs and that this activation is mediated by endothelial cell-derived ROS. In addition, endothelial cell-derived ROS are i...

show abstract

Myocardial Remodeling in Viral Heart Disease: Possible Interactions Between Inflammatory Mediators and MMP-TIMP System

Cited by 50 publications

References 112 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

Inhibition of Urokinase-Type Plasminogen Activator or Matrix Metalloproteinases Prevents Cardiac Injury and Dysfunction During Viral Myocarditis

Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species

Contact Info

Product

Resources

About