CC chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells

Nasreen S. Haque, Xiaoxia Zhang, Deborah L. French, Jihong Li, Michael Poon, John T. Fallon, Brent R. Gabel, Mark B. Taubman, Marlys Koschinsky, Peter C. Harpel

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Background - Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerosis; however, the mechanisms are unclear. We previously reported that Lp(a) stimulated human vascular endothelial cells to produce monocyte chemotactic activity. The apolipoprotein(a) [apo(a)] portion of Lp(a) was the active moiety. Methods and Results - We now describe the identification of the chemotactic activity as being due to the CC chemokine I-309. The carboxy-terminal domain of apo(a) containing 6 type-4 kringles (types 5 to 10), kringle V, and the protease domain was demonstrated to contain the I-309 - inducing portion. Polyclonal and monoclonal anti - I-309 antibodies as well as an antibody against a portion of the extracellular domain of CCR8, the I-309 receptor, inhibited the increase in monocyte chemotactic activity induced by apo(a). I-309 antisense oligonucleotides also inhibited the induction of endothelial monocyte chemotactic activity by apo(a). I-309 mRNA was identified in human umbilical vein endothelial cells. Apo(a) induced an increase in I-309 protein in the endothelial cytoplasm and in the conditioned medium. Immunohistochemical studies have identified I-309 in endothelium, macrophages, and extracellular areas of human atherosclerotic plaques and have found that I-309 colocalized with apo(a). Conclusions - These data establish that I-309 is responsible for the monocyte chemotactic activity induced in human umbilical vein endothelial cells by Lp(a). The identification of the endothelial cell as a source for I-309 suggests that this chemokine may participate in vessel wall biology. Our data also suggest that I-309 may play a role in mediating the effects of Lp(a) in artherosclerosis.

Original languageEnglish
Pages (from-to)786-792
Number of pages7
JournalCirculation
Volume102
Issue number7
DOIs
StatePublished - 2000

Keywords

  • Atherosclerosis
  • Lipoproteins
  • Peptides

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