Abstract
Background:
Kawasaki disease (KD) can result in fatal coronary artery (CA) aneurysms, especially if left untreated. Our recent studies of its vascular pathology revealed subacute/chronic vasculitis that begins early in the illness with the proliferation of smooth muscle cell–derived myofibroblasts in a complex extracellular matrix (ECM). We hypothesized that a dysregulation of specific ECM and adhesion molecules occurs in KD CAs.
Methods:
Gene expression profiling for ECM and adhesion molecules was performed on six acute KD and eight control CAs using a targeted real-time PCR array approach.
Results:
Integrins α4 and αM (ITGA4, ITGAM), collagen type I, α1 (COL1A1), and matrix metalloproteinase 7 (MMP7) were significantly upregulated in KD CAs as compared with controls. Immunohistochemistry with anti-ITGAM antibodies revealed expression on inflammatory cells within the CA wall in patients with KD but not in controls.
Conclusion:
Integrins ITGA4 and ITGAM are upregulated in KD vasculopathy, probably promoting inflammatory recruitment that stimulates smooth muscle cell transition to myofibroblasts and their proliferation. MMP7 probably enhances myofibroblast proliferation and luminal lesion expansion, and overexpression of COL1A1 may lead to CA stenosis. Identification of the molecular pathogenesis of KD vasculopathy may lead to the development of circulating biomarkers and to directed therapeutic interventions.
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References
Pham MX, Teuteberg JJ, Kfoury AG, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med 2010;362:1890–900.
Deng MC, Eisen HJ, Mehra MR, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant 2006;6:150–60.
Kittleson MM, Minhas KM, Irizarry RA, et al. Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure. Physiol Genomics 2005;21:299–307.
Tan FL, Moravec CS, Li J, et al. The gene expression fingerprint of human heart failure. Proc Natl Acad Sci USA 2002;99:11387–92.
Orenstein JM, Shulman ST, Fox LM, et al. Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. PLoS ONE 2012;7:e38998.
Fukazawa R, Ikegam E, Watanabe M, et al. Coronary artery aneurysm induced by Kawasaki disease in children show features typical senescence. Circ J 2007;71:709–15.
Takada Y, Ye X, Simon S . The integrins. Genome Biol 2007;8:215.
Avraamides CJ, Garmy-Susini B, Varner JA . Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 2008;8:604–17.
Cantor JM, Ginsberg MH, Rose DM . Integrin-associated proteins as potential therapeutic targets. Immunol Rev 2008;223:236–51.
Hom G, Graham RR, Modrek B, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 2008;358:900–9.
Simon DI, Dhen Z, Seifert P, Edelman ER, Ballantyne CM, Rogers C . Decreased neointimal formation in Mac-1(-/-) mice reveals a role for inflammation in vascular repair after angioplasty. J Clin Invest 2000;105:293–300.
Wang Y, Sakuma M, Chen Z, et al. Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury. Circulation 2005;112:2993–3000.
Abe J, Ebata R, Jibiki T, Yasukawa K, Saito H, Terai M . Elevated granulocyte colony-stimulating factor levels predict treatment failure in patients with Kawasaki disease. J Allergy Clin Immunol 2008;122:1008–1013.e8.
Kitayama J, Fuhlbrigge RC, Puri KD, Springer TA . P-selectin, L-selectin, and alpha 4 integrin have distinct roles in eosinophil tethering and arrest on vascular endothelial cells under physiological flow conditions. J Immunol 1997;159:3929–39.
Johnston B, Issekutz TB, Kubes P . The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo. J Exp Med 1996;183:1995–2006.
Garmy-Susini B, Avraamides CJ, Schmid MC, et al. Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res 2010;70:3042–51.
Lenk GM, Tromp G, Weinsheimer S, Gatalica Z, Berguer R, Kuivaniemi H . Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms. BMC Genomics 2007;8:237.
Bernstein D, Williams GE, Eisen H, et al. Gene expression profiling distinguishes a molecular signature for grade 1B mild acute cellular rejection in cardiac allograft recipients. J Heart Lung Transplant 2007;26:1270–80.
Coussens LM, Werb Z . Inflammation and cancer. Nature 2002;420:860–7.
Popper SJ, Shimizu C, Shike H, et al. Gene-expression patterns reveal underlying biological processes in Kawasaki disease. Genome Biol 2007;8:R261.
Lee Y, Schulte DJ, Shimada K, et al. Interleukin-1ß is crucial for the induction of coronary artery inflammation in a mouse model of Kawasaki disease. Circulation 2012;125:1542–50.
Newby AC, Zaltsman AB . Molecular mechanisms in intimal hyperplasia. J Pathol 2000;190:300–9.
Busiek DF, Baragi V, Nehring LC, Parks WC, Welgus HG . Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. J Immunol 1995;154:6484–91.
Swee M, Wilson CL, Wang Y, McGuire JK, Parks WC . Matrix metalloproteinase-7 (matrilysin) controls neutrophil egress by generating chemokine gradients. J Leukoc Biol 2008;83:1404–12.
Parks WC, Wilson CL, López-Boado YS . Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004;4:617–29.
Wielockx B, Libert C, Wilson C . Matrilysin (matrix metalloproteinase-7): a new promising drug target in cancer and inflammation? Cytokine Growth Factor Rev 2004;15:111–5.
Nilsson L, Jonasson L, Nijm J, Hamsten A, Eriksson P . Increased plasma concentration of matrix metalloproteinase-7 in patients with coronary artery disease. Clin Chem 2006;52:1522–7.
Bäck M, Ketelhuth DF, Agewall S . Matrix metalloproteinases in atherothrombosis. Prog Cardiovasc Dis 2010;52:410–28.
Kurokawa S, Arimura Y, Yamamoto H, et al. Tumour matrilysin expression predicts metastatic potential of stage I (pT1) colon and rectal cancers. Gut 2005;54:1751–8.
Kuhlmann KF, van Till JW, Boermeester MA, et al. Evaluation of matrix metalloproteinase 7 in plasma and pancreatic juice as a biomarker for pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2007;16:886–91.
Roy R, Yang J, Moses MA . Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol 2009;27:5287–97.
Brown TJ, Crawford SE, Cornwall ML, Garcia F, Shulman ST, Rowley AH . CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease. J Infect Dis 2001;184:940–3.
Gavin PJ, Crawford SE, Shulman ST, Garcia FL, Rowley AH . Systemic arterial expression of matrix metalloproteinases 2 and 9 in acute Kawasaki disease. Arterioscler Thromb Vasc Biol 2003;23:576–81.
Storey JD . A direct approach to false discovery rates. J R Stat Soc Series B Stat Methodol 2002;64:479–98.
Storey JD, Taylor JE, Siegmund D . Strong control, conservative point estimation and simultaneous conservative consistency of false discovery rates: a unified approach. J R Stat Soc Series B Stat Methodol 2004;66:187–205.
Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003;100:9440–5.
Acknowledgements
We thank Robin Biggs, Deidre Anderson, and Leslie Martin for assistance in identifying and dissecting control CA samples.
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Reindel, R., Baker, S., Kim, KY. et al. Integrins α4 and αM, collagen1A1, and matrix metalloproteinase 7 are upregulated in acute Kawasaki disease vasculopathy. Pediatr Res 73, 332–336 (2013). https://doi.org/10.1038/pr.2012.185
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DOI: https://doi.org/10.1038/pr.2012.185
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