Evidence suggests that aggregated low density lipoprotein (AgLDL) accumulat
es in atherosclerotic lesions. Previously, we showed that AgLDL induces and
enters surface-connected compartments (SCC) in human monocyte-derived macr
ophages by a process we have named patocytosis, Most AgLDL taken up by thes
e macrophages in the absence of serum is stored in SCC and remains undegrad
ed, We now show that macrophages released AgLDL (prepared by vortexing or t
reatment with phospholipase C or sphingomyelinase) from their SCC when expo
sed to 10% human lipoprotein-deficient serum (LPDS), Macrophages also took
up AgLDL in the presence of LPDS, but subsequently released it. In both cas
es, the released AgLDL was disaggregated, Although the AgLDL that macrophag
es took up could not pass through a 0.45-mum filter, >60% of AgLDL could pa
ss this filter after release from the macrophages. Disaggregation of AgLDL
was verified by gel-filtration chromatography and electron microscopy that
also showed particles larger than LDL, reflecting fusion of LDL that aggreg
ates. The factor in serum that mediated AgLDL release and disaggregation wa
s plasmin generated from plasminogen by macrophage urokinase plasminogen ac
tivator. AgLDL release was decreased >90% by inhibitors of plasmin (E-amino
caproic acid and antiplasminogen mAb), and also by inhibitors of urokinase
plasminogen activator (plasminogen activator inhibitor-1 and anti-urokinas
e plasminogen activator mAb), Moreover, plasminogen could substitute for LP
DS and produce similar macrophage release and disaggregation of AgLDL. Beca
use only plasmin bound to the macrophage surface is protected from serum pl
asmin inhibitors, interaction of AgLDL with macrophages was necessary for r
eversal of its aggregation by LPDS. The released disaggregated LDL particle
s were competent to stimulate LDL receptor-mediated endocytosis in cultured
fibroblasts, Macrophage-mediated disaggregation of aggregated and fused LD
L is a mechanism for transforming LDL into lipoprotein structures size-cons
istent with lipid particles found in atherosclerotic lesions.