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

Background-Lipoprotein(a) [Lp(a)] is a risk factor for atherosclerosis; how ever, the mechanisms are unclear. We previously reported that Lp(a) stimula ted human vascular endothelial cells to produce monocyte chemotactic activi ty, The apolipoprotein(a) [apo(a)] portion of Lp(a) was the active moiety. Methods and Results-We now describe the identification of the chemotactic a ctivity 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. Po lyclonal and monoclonal anti-I-309 antibodies as well as an antibody agains t a portion of the extracellular domain of CCR8, the I-309 receptor, inhibi ted the increase in monocyte chemotactic activity induced by apo(a). I-309 antisense oligonucleotides also inhibited the induction of endothelial mono cyte chemotactic activity by apo(a). I-309 mRNA was identified in human umb ilical vein endothelial cells. Apo(a) induced an increase in I-309 protein in the endothelial cytoplasm and in the conditioned medium. Immunohistochem ical studies have identified I-309 in endothelium, macrophages, and extrace llular areas of human atherosclerotic plaques and have found that I-309 col ocalized 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 sug gests 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) i n atherosclerosis.