Chemokine receptor-8: potential role in atherogenesis

Chemokines and their receptors play regulatory roles in inflammatory reactions. Lipoprotein(a) is an atherogenic lipoprotein, however the mechanisms of its actions are not defined. Our interest in chemokines and their receptors was stimulated by the finding that incubation of Lp(a) with human umbilical vein endothelial cells produced a conditioned medium that was chemotactic for human monocytes. Since infiltration of monocytes into the vessel wall is an early lesion in atherosclerosis, this finding provided a novel mechanism to explain the relationship between Lp(a) and atherosclerosis. The chemoattractant produced by HUVEC was identified as CCL1/I-309, a CC chemokine previously reported to be secreted by stimulated monocytes/macrophages and T lymphocytes. CCR8, the CCL1 receptor, was identified on endothelial cells, and CCL1 was found to be a chemoattractant for these cells. Most recently we demonstrated functional CCR8 on human vascular smooth muscle cells and found that the Lp(a)-HUVEC conditioned medium is a chemoattractant for these cells. CCL1 increased metalloproteinase-2 production by HUVEC, an activity that enables these cells to remodel the vascular matrix. These studies suggest that CCR8 may play an important role in arterial wall pathology.