765-4 Adhesiveness of Mononuclear Cells is Increased in Hypercholesterolemic Humans, and Reduced by the NO Precursor

Abstract

Enhanced interaction of mononuclear cells with the endothelium is the first observable event in the development of atherosclerosis. Hypercholesterolemia reduces vascular nitric oxide activity. This dysfunction may promote endothelial monocyte interaction, as NO is a potent inhibitor of adhesion. We have previously shown that dietary L-arginine (Arg) supplementation in hypercholesterolemic rabbits restores NO activity and inhibits monocyte-endothelial cell interaction, in association with a reduction in atherogenesis. Accordingly we developed a functional binding assay to assess the adhesiveness of human mononuclear cells, so as to determine the effects of hypercholesterolemia and L-arginine therapy. We found a 50% increase in adhesion of mononuclear cells (MNC) from hypercholesterolemic (HC) subjects to cultured endothelial cells ex vivo compared to a normocholesterolemic control population (p < 0.0001, n = 20). Increased MNC adhesion was reversed to normal levels by preincubation of the MNC suspension with 10 -5 M sodium nitroprusside (164.4 ± 8.7% vs 97.5 ± 6.9%, P < 0.0005, n = 7), while L-nitroarginine and Arg did not have an effect in vitro . In a double-blinded placebo-controlled study, oral Arg (8.4 g/day) was administered to 7 HC subjects. Over a course of two weeks, this treatment abolished the increased adhesion (158.5 ± 10.9% vs 103.5 ± 4.9% vs 100 ± 5.2%, HCvs Arg vs Control. p < 0.005), while MNC adhesion remained significantly elevated in placebo-treated subjects. The adhesiveness of human mononuclear cells is increased by hypercholesterolemia. The increase in adhesiveness is reversed in vitro by NO donors, and reversed in vivo by treatment with the NO precursor L-arginine.