(Circulation. 2000;102:786.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
CC Chemokine I-309 Is the Principal Monocyte Chemoattractant Induced by Apolipoprotein(a) in Human Vascular Endothelial Cells
From the Division of Hematology, Department of Medicine (N.S.H., X.Z., D.L.F., J.L., P.C.H.), and the Zena and Michael A. Weiner Cardiovascular Institute (M.P., J.T.F., M.B.T.), Mount Sinai School of Medicine, New York, NY, and the Department of Biochemistry (B.R.G., M.K.), Queen’s University, Kingston, Ontario, Canada.
Correspondence to Peter C. Harpel, MD, Box 1079, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. E-mail peter.harpel{at}mssm.edu
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 atherosclerosis.
Key Words: lipoproteins • atherosclerosis • peptides
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