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Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease.

Kentsis A, Shulman A, Ahmed S, Brennan E, Monuteaux MC, Lee YH, Lipsett S, Paulo JA, Dedeoglu F, Fuhlbrigge R, Bachur R, Bradwin G, Arditi M, Sundel RP, Newburger JW, Steen H, Kim S - EMBO Mol Med (2012)

Bottom Line: We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A.Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients.Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

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Meprin A is enriched in coronary artery lesions in a mouse model of Kawasaki diseaseA,B. Micrographs of hematoxylin and eosin-stained sections of the aortic root and coronary arteries of control (A) and LCWE-injected mice (B) demonstrating severe aortitis with intimal proliferation leading to concentric obstruction in the LCWE-injected but not control animals. Arrows point to the normal (A) and diseased (B) coronary arteries.C,D. Micrographs of meprin A immunohistochemistry-stained inset areas of the sections of coronary arteries demonstrating enrichment of meprin A in the mononuclear infiltrates of coronary arteries in LCWE-injected (D) but not control (C) animals.E,F. Micrographs of isotype control-stained sections of coronary arteries in LCWE-injected (F) and control (E) mice.G,H. High-magnification micrographs of the inset areas of meprin A (G) and isotype control-strained (H) sections of the coronary arteries in LCWE-injected mice.I,J. Serum levels of meprin A (I) and filamin (J) are elevated in the LCWE-injected (red) as compared to control (green) mice. Scale bar is 250 µM.
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fig04: Meprin A is enriched in coronary artery lesions in a mouse model of Kawasaki diseaseA,B. Micrographs of hematoxylin and eosin-stained sections of the aortic root and coronary arteries of control (A) and LCWE-injected mice (B) demonstrating severe aortitis with intimal proliferation leading to concentric obstruction in the LCWE-injected but not control animals. Arrows point to the normal (A) and diseased (B) coronary arteries.C,D. Micrographs of meprin A immunohistochemistry-stained inset areas of the sections of coronary arteries demonstrating enrichment of meprin A in the mononuclear infiltrates of coronary arteries in LCWE-injected (D) but not control (C) animals.E,F. Micrographs of isotype control-stained sections of coronary arteries in LCWE-injected (F) and control (E) mice.G,H. High-magnification micrographs of the inset areas of meprin A (G) and isotype control-strained (H) sections of the coronary arteries in LCWE-injected mice.I,J. Serum levels of meprin A (I) and filamin (J) are elevated in the LCWE-injected (red) as compared to control (green) mice. Scale bar is 250 µM.

Mentions: Since meprin A is a protease that regulates a variety of immune cytokines, we investigated the potential involvement of meprin A in the pathogenesis of Kawasaki disease using a mouse model of coronary arteritis that reproduces several features of KD (Lehman et al, 1988). In particular, moribund mice develop systemic mononuclear vasculitis that leads to myocarditis, aortitis and coronary arteritis with intimal proliferation, characteristic of Kawasaki disease. Using immunohistochemical analysis, we found that meprin A was enriched in the vascular lesions of mice with coronary arteritis but not in control mice using specific meprin A antibodies (Fig 4A–H). Likewise, we found that levels of circulating meprin A and filamin C were significantly elevated in the serum of mice with coronary arteritis as compared to control mice (mean 4.7 vs. 0.3 ng/ml, and 107.2 vs. 1.4 ng/ml, two-tailed t-test p = 0.0053 and 0.00098, respectively, Fig 4I and J).


Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease.

Kentsis A, Shulman A, Ahmed S, Brennan E, Monuteaux MC, Lee YH, Lipsett S, Paulo JA, Dedeoglu F, Fuhlbrigge R, Bachur R, Bradwin G, Arditi M, Sundel RP, Newburger JW, Steen H, Kim S - EMBO Mol Med (2012)

Meprin A is enriched in coronary artery lesions in a mouse model of Kawasaki diseaseA,B. Micrographs of hematoxylin and eosin-stained sections of the aortic root and coronary arteries of control (A) and LCWE-injected mice (B) demonstrating severe aortitis with intimal proliferation leading to concentric obstruction in the LCWE-injected but not control animals. Arrows point to the normal (A) and diseased (B) coronary arteries.C,D. Micrographs of meprin A immunohistochemistry-stained inset areas of the sections of coronary arteries demonstrating enrichment of meprin A in the mononuclear infiltrates of coronary arteries in LCWE-injected (D) but not control (C) animals.E,F. Micrographs of isotype control-stained sections of coronary arteries in LCWE-injected (F) and control (E) mice.G,H. High-magnification micrographs of the inset areas of meprin A (G) and isotype control-strained (H) sections of the coronary arteries in LCWE-injected mice.I,J. Serum levels of meprin A (I) and filamin (J) are elevated in the LCWE-injected (red) as compared to control (green) mice. Scale bar is 250 µM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3569638&req=5

fig04: Meprin A is enriched in coronary artery lesions in a mouse model of Kawasaki diseaseA,B. Micrographs of hematoxylin and eosin-stained sections of the aortic root and coronary arteries of control (A) and LCWE-injected mice (B) demonstrating severe aortitis with intimal proliferation leading to concentric obstruction in the LCWE-injected but not control animals. Arrows point to the normal (A) and diseased (B) coronary arteries.C,D. Micrographs of meprin A immunohistochemistry-stained inset areas of the sections of coronary arteries demonstrating enrichment of meprin A in the mononuclear infiltrates of coronary arteries in LCWE-injected (D) but not control (C) animals.E,F. Micrographs of isotype control-stained sections of coronary arteries in LCWE-injected (F) and control (E) mice.G,H. High-magnification micrographs of the inset areas of meprin A (G) and isotype control-strained (H) sections of the coronary arteries in LCWE-injected mice.I,J. Serum levels of meprin A (I) and filamin (J) are elevated in the LCWE-injected (red) as compared to control (green) mice. Scale bar is 250 µM.
Mentions: Since meprin A is a protease that regulates a variety of immune cytokines, we investigated the potential involvement of meprin A in the pathogenesis of Kawasaki disease using a mouse model of coronary arteritis that reproduces several features of KD (Lehman et al, 1988). In particular, moribund mice develop systemic mononuclear vasculitis that leads to myocarditis, aortitis and coronary arteritis with intimal proliferation, characteristic of Kawasaki disease. Using immunohistochemical analysis, we found that meprin A was enriched in the vascular lesions of mice with coronary arteritis but not in control mice using specific meprin A antibodies (Fig 4A–H). Likewise, we found that levels of circulating meprin A and filamin C were significantly elevated in the serum of mice with coronary arteritis as compared to control mice (mean 4.7 vs. 0.3 ng/ml, and 107.2 vs. 1.4 ng/ml, two-tailed t-test p = 0.0053 and 0.00098, respectively, Fig 4I and J).

Bottom Line: We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A.Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients.Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Show MeSH
Related in: MedlinePlus