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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3970-3978. Prepublished online as a Blood First Edition Paper on August 11, 2005; DOI 10.1182/blood-2005-03-1292. This Article Full Text (PDF) All Versions of this Article: 2005-03-1292v1 106/12/3970    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Pluskota, E. Articles by Plow, E. F Search for Related Content PubMed PubMed Citation Articles by Pluskota, E. Articles by Plow, E. F Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 30, 2005 Accepted July 28, 2005 The mechanism and impact of thrombospondin-4 polymorphisms on neutrophil function Elzbieta Pluskota, Olga I Stenina, Irene Krukovets, Dorota Szpak, Eric J Topol, and Edward F Plow* Joseph Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Foundation, Cleveland, OH, USA * Corresponding author; email: plowe{at}ccf.org. High-throughput genomic technology identified an association between a single nucleotide polymorphism (SNP), a proline (P387) rather than the predominant alanine (A387) at position 387 in thrombospondin-4 (TSP-4), and premature myocardial infarction. The inflammatory hypothesis of atherosclerosis invokes a prominent role of leukocytes and cytokines in pathogenesis. As the expression of TSP-4 by vascular cells permits its exposure to circulating leukocytes, the interactions of human neutrophils (PMN) with both TSP-4 variants were investigated. PMA-stimulated PMNs adhered and migrated well and equally on the TSP-4 variants. Integrin M2 was identified as the TSP-4 receptor mediating these responses and the 3 EGF-like domains of TSP-4 harboring the SNPs interacted with the MI-domain. Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related MAPKs: p38MAPK and JNK, as well as STAT1 and HSP27 than the A387 variant. Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more IL-8 as compared to the A387. H2O2 release and p38MAPK activation were totally inhibited by blockade of M2. Thus, M2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Pluskota, N. M. Woody, D. Szpak, C. M. Ballantyne, D. A. Soloviev, D. I. Simon, and E. F. Plow Expression, activation, and function of integrin {alpha}M{beta}2 (Mac-1) on neutrophil-derived microparticles Blood, September 15, 2008; 112(6): 2327 - 2335. [Abstract] [Full Text] [PDF] W. Koch, P. Hoppmann, A. de Waha, A. Schomig, and A. Kastrati Polymorphisms in thrombospondin genes and myocardial infarction: a case-control study and a meta-analysis of available evidence Hum. Mol. Genet., April 15, 2008; 17(8): 1120 - 1126. [Abstract] [Full Text] [PDF] M. Caceres, C. Suwyn, M. Maddox, J. W. Thomas, and T. M. Preuss Increased Cortical Expression of Two Synaptogenic Thrombospondins in Human Brain Evolution Cereb Cortex, October 1, 2007; 17(10): 2312 - 2321. [Abstract] [Full Text] [PDF] O. I. Stenina, E. J. Topol, and E. F. Plow Thrombospondins, Their Polymorphisms, and Cardiovascular Disease Arterioscler Thromb Vasc Biol, September 1, 2007; 27(9): 1886 - 1894. [Abstract] [Full Text] [PDF] E. J. Topol, J. Smith, E. F. Plow, and Q. K. Wang Genetic susceptibility to myocardial infarction and coronary artery disease Hum. Mol. Genet., October 15, 2006; 15(suppl_2): R117 - R123. [Abstract] [Full Text] [PDF]

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