Journal
BLOOD
Volume 106, Issue 12, Pages 3970-3978Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2005-03-1292
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Funding
- NHLBI NIH HHS [P50 HL-077107, R01 HL 66197] Funding Source: Medline
- NIDDK NIH HHS [K01DK62128] Funding Source: Medline
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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 1 of TSP-4 by vascular cells permits its exposure to circulating leukocytes, the interactions of human neutrophils (polymorphonuclear leukocytes [PMNs]) with both TSP-4 variants were investigated. Phorbol 12-myristate 13-acetate (PMA)stimulated PMNs adhered and migrated well and equally on the TSP-4 variants. Integrin alpha(M)beta(2) was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)-like domains of TSP-4 harboring the SNPs interacted with the alpha(M)l-domain. Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JINK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant. Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387. H2O2 release and p38MAPK activation were totally inhibited by blockade Of alpha O-M(2). Thus, alpha O-M(2) plays a central role in proinflammatory activities of TSP-4 (13387) and may contribute to the prothrombotic phenotype associated with this variant.
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