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

Citation
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
Citations number
63
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
274
Issue
8
Year of publication
1999
Pages
4816 - 4823
Database
ISI
SICI code
0021-9258(19990219)274:8<4816:AECHDL>2.0.ZU;2-7
Abstract
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.