Low density lipoproteins in human plasma make vascular smooth muscle cells resistant to growth inhibition by heparin.

Abstract

Vascular smooth muscle cell hyperplasia plays a role in atherosclerosis and restenosis. While heparin has shown promise as an inhibitor of smooth muscle cell proliferation in vitro and in some animal models, it has failed to reduce restenosis in clinical trials. We have previously shown that human smooth muscle cells grown in the presence of human serum are heparin resistant, whereas in the presence of bovine serum they are heparin sensitive. In this report, we demonstrate that the heparin resistance factor is present in human plasma as well as serum, and characterise it further. Human vascular smooth muscle cells were cultured as explants from the media of redundant adult internal mammary or umbilical cord arteries. They were tested for sensitivity to heparin at 100 microg/ml in the growth medium, in the presence of foetal bovine serum, human-plasma-derived serum, human whole blood serum, or fractions derived from these. In the presence of foetal bovine serum, heparin inhibited cell proliferation, while human-plasma-derived or whole blood sera conveyed heparin resistance. This activity was contained within the fraction of plasma/serum which bound to heparin Sepharose, and the sub-fraction which was retained by a membrane filter of molecular weight cut off of 100000. All the heparin resistance in this latter fraction was supplied by lipoproteins. LDL prepared directly from human plasma conveyed similar heparin resistance to the lipoproteins from the above sub-fraction. LDL in human plasma/serum conveys resistance to the anti-proliferative effects of heparin upon vascular smooth muscle cells. This activity may interfere with potential therapeutic effects of heparin as an anti-restenosis agent.