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

Lau, Andrew; Duong, Trang T.; Itô, Shinya; Yeung, Rae S. M.

doi:10.1002/art.23225

Cited by 74 publications

(76 citation statements)

References 34 publications

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“…39 -41 Heightened MMP-9 activity is also found in the coronary arteries of LCWE-treated animals, localizing to the vascular smooth muscle cells. 22 Interestingly, we observed an increase in active MMP-9 in the animals treated with LCWE and TGF-␤ nAb by 14 days, before the point when MMP-9 activity is increased in mice treated with LCWE alone. 22 This suggests that TGF-␤ blockade both enhances and accelerates the proteolytic process.…”

Section: Discussionmentioning

confidence: 61%

“…30,31 Furthermore, TNF-␣-mediated induction of MMP-9 activity is necessary for the elastin breakdown observed in the LCWE murine model of KD. 22 We evaluated the expression of MMP-9 by quantitative RT-PCR in the heart at 14 days and found no significant difference in MMP-9 expression in any of the four treatment groups ( Figure 8A). …”

Section: Tgf-␤ Blockade Increases Mmp-9 Activity and Reduces Pai-1 Exmentioning

confidence: 97%

“…or an equal volume of vehicle (PBS), as used previously in an accepted animal model of KD. 21,22 Mice were sacrificed at 2 and 14 days, the hearts were perfused with PBS, and then either prepared for histological analysis or snap frozen for RNA and protein extraction. At 42 days, mice were anesthetized and sacrificed by exsanguination and the coronary circulation was perfused under physiological perfusion pressure by injecting barium gelatin through the left ventricle after ligating the ascending aorta.…”

Section: Murine Model Of Kdmentioning

confidence: 99%

“…21,22,26,27 We first examined the activation of TGF-␤ in the coronary arteries by performing immunohistochemistry to detect pSmad2/3, the intracellular molecule that translocates into the nucleus in response to TGF-␤ signaling. A moderate amount of nuclear pSmad2/3 was observed in the neonatal coronary artery endothelium, adventitia, and cardiac myocytes in vehicle-treated controls 2 days after the start of the experiment ( Figure 1A).…”

Section: Lcwe Increases Tgf-␤ Signaling In the Coronary Wall And Indumentioning

confidence: 99%

“…Next, we evaluated the integrity of the coronary elastin by Hart's staining 42 days after LCWE, the point when previous studies 21,22 have demonstrated that LCWE causes elastin breakdown, an early feature of CAL. Compared with vehicle controls, the coronary arteries of the LCWEtreated mice demonstrated thinning and flattening of the internal elastic lamina and fraying of the external elastic lamina, with multiple areas of fragmentation (Figure 2A).…”

Section: Lcwe Induces Fragmentation Of the Coronary Artery Elastinmentioning

confidence: 99%

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Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Alvira

Guignabert

Kim

et al. 2011

The American Journal of Pathology

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Kawasaki disease (KD) is an acute inflammatory illness marked by coronary arteritis. However, the factors increasing susceptibility to coronary artery lesions are unknown. Because transforming growth factor (TGF) ␤ increases elastin synthesis and suppresses proteolysis, we hypothesized that, in contrast to the benefit observed in aneurysms forming in those with Marfan syndrome, inhibition of TGF-␤ would worsen inflammatory-induced coronary artery lesions. By using a murine model of KD in which injection of Lactobacillus casei wall extract (LCWE) induces coronary arteritis, we show that LCWE increased TGF-␤ signaling in the coronary smooth muscle cells beginning at 2 days and continuing through 14 days, the point of peak coronary inflammation. By 42 days, LCWE caused fragmentation of the internal and external elastic lamina. Blocking TGF-␤ by administration of a neutralizing antibody accentuated the LCWE-mediated fragmentation of elastin and induced an overall loss of medial elastin without increasing the inflammatory response. We attributed these increased pathological characteristics to a reduction in the proteolytic inhibitor, plasminogen activator inhibitor-1, and an associated threefold increase in matrix metalloproteinase 9 activity compared with LCWE alone. Therefore, our data demonstrate that in the coronary arteritis associated with KD, TGF-␤ suppresses elastin degradation by inhibiting plasmin-mediated matrix metalloproteinase 9 activation. Thus, strategies to block TGF-␤, used in those with Marfan syndrome, are unlikely to be beneficial and could be detrimental.

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Section: Discussionmentioning

confidence: 61%

Section: Tgf-␤ Blockade Increases Mmp-9 Activity and Reduces Pai-1 Exmentioning

confidence: 97%

Section: Murine Model Of Kdmentioning

confidence: 99%

Section: Lcwe Increases Tgf-␤ Signaling In the Coronary Wall And Indumentioning

confidence: 99%

Section: Lcwe Induces Fragmentation Of the Coronary Artery Elastinmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Alvira

Guignabert

Kim

et al. 2011

The American Journal of Pathology

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Intravenous immunoglobulin and salicylate differentially modulate pathogenic processes leading to vascular damage in a model of Kawasaki disease

Lau¹,

Duong²,

Itô³

et al. 2009

Arthritis & Rheumatism

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Objective. Kawasaki disease (KD) is a multisystem vasculitis affecting children and is characterized by immune activation in the acute stage of disease. Systemic inflammation eventually subsides, although coronary arteritis persists, resulting in aneurysm formation. KD is the leading cause of acquired heart disease among children in North America. Accepted treatment guidelines include high-dose intravenous immunoglobulin (IVIG) and aspirin in the acute phase. Although this therapy is effective, the cellular and molecular mechanisms involved are not clear. The aim of this study was to examine the effect of IVIG and salicylate at each stage of disease development.Methods. Using a murine model of KD, we established and validated several in vitro techniques to reflect 3 key steps involved in disease pathogenesis, as follows: thymidine incorporation to evaluate T cell activation, enzyme-linked immunosorbent assay to measure tumor necrosis factor ␣ (TNF␣) production, and realtime polymerase chain reaction to examine TNF␣-mediated expression of matrix metalloproteinase 9 (MMP-9).Results. At therapeutic concentrations, IVIG, but not salicylate, effectively reduced the immune response leading to TNF␣ expression. Unexpectedly, pharmacologic doses of salicylate were not able to inhibit TNF␣ production and in fact enhanced its production. Neither drug directly regulated MMP-9 expression but did so only indirectly via modulating TNF␣. TNF␣ activity was a prerequisite for local expression of MMP-9 at the coronary artery.Conclusion. Therapeutic concentrations of IVIG and salicylate differentially modulate the expression of TNF␣ and its downstream effects. Further dissection of the biologic effects of aspirin in acute KD is necessary for the rational design of therapy.

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Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin–Resistant Kawasaki Disease

Koné‐Paut

Tellier

Belot

et al. 2020

Arthritis & Rheumatology

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Objective. Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies of intravenous immunoglobulin (IVIG)and steroid-resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin-1 in patients with IVIG-resistant KD. Methods. Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. The starting dose was 2 mg/kg of anakinra (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient's body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. The primary outcome was abatement of fever. Secondary outcome measures included disease activity, coronary artery Z score, and C-reactive protein (CRP) levels. Results. Seventy-five percent of the patients in the intent-to-treat group and 87.5% in the per-protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% of physician evaluations (95% confidence interval [95% CI] 68.1-99.8%) and on 100% of parent evaluations (95% CI 73.5-100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. On day 45, 5 of 10 patients (50% [95% CI 18.7-81.3%]) and 6 of 12 patients (50% [95% CI 21.1-78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred. Conclusion. Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG-refractory KD.

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

Cited by 74 publications

References 34 publications

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Inhibition of Transforming Growth Factor β Worsens Elastin Degradation in a Murine Model of Kawasaki Disease

Intravenous immunoglobulin and salicylate differentially modulate pathogenic processes leading to vascular damage in a model of Kawasaki disease

Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin–Resistant Kawasaki Disease

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