Abstract 1331: Identification of a Novel Regulator of Lipid Accumulation of Macrophages Secreted from Intimal Smooth Muscle Cells
Macrophage is an important regulator for plaque stability through multiple functions including lipid accumulation in the course of atherosclerosis. Here, we show a novel regulator of lipid accumulation in macrophages which is secreted from intimal smooth muscle cells (SMCs). This molecule is LR11, a member of the LDL receptor family, and highly expressed in SMCs of the hyperplastic intima as a secreted soluble form (solLR11) as well as a membrane-bound form. The solLR11 shows a potent enhancement of migration for SMCs through the activation of urokinase receptor (uPAR) system. Immunochemical analyses showed that secreted solLR11 is abundantly expressed in the thickened intima after balloon injury, particularly around intimal SMCs, and the expression was extremely at high level in the early stage of neointimal formation. In order to know the effects of solLR11 on macrophage functions in atherosclerotic intima, we prepared an active recombinant solLR11 protein by using the transfection of cDNA lacking a membrane spanning region into mammalian cells. The incubation of THP-1 cells, an established monocyte-macrophage cell line, with the purified recombinant solLR11 expectedly enhanced migration activities in the presence of PDGF-BB. In accordance with the increase in migration activity, solLR11 significantly increased adhesion activity of THP-1 macrophages to extracellular matrices, such as fibronectin and collagen, and also to cultured SMCs. Furthermore, solLR11 drastically enhanced the expression level of macrophage scavenger receptor on cell membrane of THP-1 stimulated by PMA. Uptake of Acetyl (Ac) -LDL by THP-1 was significantly increased in the presence of solLR11. Finally the effects of solLR11 on migration, adhesion and Ac-LDL uptake were blocked by the addition of anti-uPAR neutralization antibody. In conclusion, solLR11, secreted specifically from intimal SMCs, regulates adhesion, migration and lipid accumulation of macrophages through the activation of uPAR system on macrophages. Lipid incorporation into macrophages is possibly regulated by intimal SMCs in atherosclerotic plaques.