Circulating Matrix Metalloproteinases and Their Inhibitors in Patients with Kawasaki Disease

Senzaki, Hideaki; Masutani, Satoshi; Kobayashi, Jun; Kobayashi, Toshiki; Nakano, Hirofumi; Nagasaka, Hironori; Sasaki, Nozomu; Asano, Haruhiko; Kyo, Shunei; Yokote, Yuji

doi:10.1161/hc3301.095286

Cited by 88 publications

(71 citation statements)

References 13 publications

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“…But despite the fact that MMP-9 levels were elevated in affected hearts in our murine model of KD, there was no correlation between circulating MMP-9 levels and enzymatic activity in affected coronary arteries (25). This is in accordance with data from cases of fatal KD, which show MMP-9 expression specifically localized to the site of coronary artery lesions (26), and the conflicting reports regarding circulating MMP-9 levels in affected children (22)(23)(24)(25). Degradation of elastin is one of the hallmarks of aneurysm formation.…”

Section: Discussionsupporting

confidence: 86%

“…MMP-9 may have a role in coronary artery aneurysm formation in KD. Despite conflicting data on serum levels of MMP-9 during the acute phase of KD (22)(23)(24)(25), local MMP-9 expression at the site of coronary artery aneurysms in children with KD has been documented (26). Circulating levels of molecules known to act locally may not be useful biomarkers of disease; this is especially relevant to enzymatic activity, which is tightly regulated at multiple levels including the local tissue environment (25).…”

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confidence: 99%

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Matrix metalloproteinase 9 activity leads to elastin breakdown in an animal model of Kawasaki disease

Lau¹,

Duong²,

Itô³

et al. 2008

Arthritis & Rheumatism

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Objective. Kawasaki disease (KD) is a multisystem vasculitis leading to damage in the coronary circulation and aneurysm formation. Because cardiac tissue from affected children is not available, investigation of the mechanisms responsible for coronary artery damage in KD requires use of a disease model. The present study was undertaken to examine, in an experimental model, the role of matrix metalloproteinase 9 (MMP-9) on coronary artery inflammation and vascular damage.Methods. C57BL/6 mice were injected with Lactobacillus casei cell wall extract to induce coronary arteritis. Hearts were isolated and assayed for MMP-9 protein expression and enzymatic activity by immunoblotting or confocal microscopy and zymography, respectively. MMP-9-deficient mice were used to examine the necessity of MMP-9 for disease development.Results. Localized inflammation at the coronary artery led to elastin breakdown and aneurysm formation. This occurred in the absence of smooth muscle cell apoptosis. Following disease induction, there was an increase in the amount and enzymatic activity of MMP-9, an elastolytic protease. MMP-9 was upregulated by tumor necrosis factor ␣ (TNF␣) and produced primarily by vascular smooth muscle cells. In MMP-9-deficient animals, vascular inflammation continued to develop, but the incidence of elastin breakdown was significantly reduced. Elastin breakdown in the coronary artery was virtually eliminated by ablation of MMP-9.Conclusion. These findings show that TNF␣ upregulates expression of MMP-9, an important proteinase responsible for extracellular matrix breakdown, leading to coronary artery damage in this model of KD. These results have important implications regarding treatments for improving coronary outcome in affected children.

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Section: Discussionsupporting

confidence: 86%

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confidence: 99%

Matrix metalloproteinase 9 activity leads to elastin breakdown in an animal model of Kawasaki disease

Lau¹,

Duong²,

Itô³

et al. 2008

Arthritis & Rheumatism

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“…The plasma levels of neutrophil elastase and myeloperoxidase (MPO) were reported to be increased in the acute phase of KD [11]. Furthermore, the plasma levels of neutrophil elastase were reported to be higher in patients with CAL than in those without CAL [19]. Biezeveld et al reported that the plasma levels of neutrophil elastase remained high from the acute phase of KD throughout the convalescent phase (three months after the onset), suggesting that neutrophil activation may be sustained for longer than was previously assumed [20].…”

Section: The Increased Number Of Neutrophils and The Morphological Chmentioning

confidence: 99%

The Role of Neutrophil Activation in the Pathogenesis of Kawasaki Disease

Takeshita¹,

Kawamura²,

Kanai³

et al. 2018

Pediatric Infect Dis

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In the acute phase of Kawasaki disease (KD), there is an increase in the number of circulating neutrophils, including toxic neutrophils, which are caused by a morphological change. The functions of the neutrophils are also activated, leading to the excessive production of reactive oxygen species and elastase, which may induce endothelial cell (EC) injury. Histological findings demonstrate that numerous neutrophils infiltrate into coronary artery lesions (CALs) during the early phase of KD. Thus, it is suggested that neutrophil-mediated EC injury may be involved in the formation of CALs in KD patients. In this review, we focus on the role of neutrophil activation in the pathogenesis of KD vasculitis and discuss the methods of treatment for neutrophil-mediated EC injury.

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“…Cardiac myocyte hypertrophy occurs during developmental growth of the heart (1) and is induced in response to exercise or pathological conditions (1)(2)(3). Conversely, the heart can undergo reduction in size in response to starvation, as observed in patients with anorexia nervosa (4,5), or with decreased work load, as occurs with implantation of left ventricular assist device (6,7). Therefore, multiple stimuli can affect heart size, and maintenance of proper cardiomyocyte size is critical for normal cardiac function.…”

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confidence: 99%