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J Biol Chem, Vol. 274, Issue 8, 4816-4823, February 19, 1999

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

From the Division of Preventive Medicine and Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032

Reduced heparin and heparan sulfate (HS) proteoglycans (PG) have been observed in both inflammation and atherosclerosis. Methods to increase endogenous heparin and heparan sulfate are not known. We found that incubation of endothelial cells with 500-1,000 µg/ml high density lipoprotein (HDL) increased ³⁵SO₄ incorporation into PG by 1.5-2.5-fold. A major portion of this increase was in HS and was the result of increased synthesis. Total PG core proteins were not altered by HDL; however, the ratio of ³⁵SO₄ to [³H]glucosamine was increased by HDL, suggesting increased sulfation of glycosaminoglycans. In addition, HDL increased the amount of highly sulfated heparin-like HS in the subendothelial matrix. HS from HDL-treated cells bound 40 ± 5% more ¹²⁵I-antithrombin III (requires 3-O sulfated HS) and 49 ± 3% fewer monocytes. Moreover, the HS isolated from HDL-treated cells inhibited 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. ApoE also stimulated HS production in the absence of HDL. ApoE did not increase ³⁵SO₄ 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 µg/ml) doses, suggesting the involvement of a receptor-associated protein-sensitive pathway in mediating apoE actions. In summary, our data identify a novel mechanism by which apoE and apoE-containing HDL can be anti-atherogenic. Identification of specific apoE peptides that stimulate endothelial heparin/HS production may have important therapeutic applications.

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