Apolipoprotein E containing high density lipoprotein stimulates endothelial production of heparan sulfate rich in biologically active heparin-like domains - A potential mechanism for the anti-atherogenic actions of vascular apolipoprotein E
L. Paka et al., Apolipoprotein E containing high density lipoprotein stimulates endothelial production of heparan sulfate rich in biologically active heparin-like domains - A potential mechanism for the anti-atherogenic actions of vascular apolipoprotein E, J BIOL CHEM, 274(8), 1999, pp. 4816-4823
Reduced heparin and heparan sulfate (HS) proteoglycans (PG) have been obser
ved in both inflammation and atherosclerosis. Methods to increase endogenou
s heparin and heparan sulfate are not known. We found that incubation of en
dothelial cells with 500-1,000 mu g/ml high density lipoprotein (HDL) incre
ased (SO4)-S-35 incorporation into PG by 1.5-2.5-fold. A major portion of t
his increase was in HS and was the result of increased synthesis. Total PG
core proteins were not altered by HDL; however, the ratio of (SO4)-S-35 to
[H-3]glucosamine was increased by HDL, suggesting increased sulfation of gl
ycosaminoglycans. In addition, HDL increased the amount of highly sulfated
heparin-like HS in the subendothelial matrix, HS from HDL-treated cells bou
nd 40 +/- 5% more I-125-antithrombin III (requires 3-O sulfated HS) and 49
+/- 3% fewer monocytes. Moreover, the HS isolated from HDL-treated cells in
hibited smooth muscle cell proliferation (by 83 +/- 5%) better than control
HS (56 +/- 6%) and heparin (42 +/- 6%). HDL isolated from apolipoprotein E
(apoE)-null mice did not stimulate HS production unless apoE was added. Ap
oE also stimulated HS production in the absence of HDL. ApoE did not increa
se (SO4)-S-35 incorporation in macrophages and fibroblasts, suggesting that
this is an endothelial cell-specific process. Receptor-associated protein
inhibited apoE-mediated stimulation of HS only at higher (20 mu g/ml) doses
, suggesting the involvement of a receptor-associated protein-sensitive pat
hway in mediating apoE actions. In summary, our data identify a novel mecha
nism by which apoE and apoE-containing HDL can be antiatherogenic. Identifi
cation of specific apoE peptides that stimulate endothelial heparin/HS prod
uction may have important therapeutic applications.