Defensin promotes the binding of lipoprotein(a) to vascular matrix

Retention of lipoproteins within the vasculature is a central event in the pathogenesis of atherosclerosis. However, the signals that mediate this pro cess are only partially understood. Prompted by putative links between infl ammation and atherosclerosis, we previously reported that cu-defensins rele ased by neutrophils are present in human atherosclerotic lesions and promot e the binding of lipoprotein(a) [Lp(a)] to vascular cells without a concomi tant increase in degradation. We have now tested the hypothesis that this a ccumulation results from the propensity of defensin to form stable complexe s with Lp(a) that divert the lipoprotein from its normal cellular degradati ve pathways to the extracellular matrix (ECM). In accord with this hypothes is, defensin stimulated the binding of Lp(a) to vascular matrices approxima tely 40-fold and binding of the reactants to the matrix was essentially irr eversible. Defensin formed stable, multivalent complexes with Lp(a) and wit h its components, apoprotein (a) and low-density lipoprotein (LDL), as asse ssed by optical biosensor analysis, gel filtration, and immunoelectron micr oscopy. Binding of defensin/Lp(a) complexes to matrix was inhibited (>90%) by heparin and by antibodies to fibronectin (>70%), but not by antibodies t o vitronectin or thrombospondin. Defensin increased the binding of Lp(a) (1 0 nmol/L) to purified fibronectin more than 30-fold. Whereas defensin and L p(a) readily traversed the endothelial cell membranes individually, defensi n/Lp(a) complexes lodged on the cell surface. These studies demonstrate tha t or-defensins released from activated or senescent neutrophils stimulate t he binding of an atherogenic lipoprotein to the ECM of endothelial cells, a process that may contribute to lipoprotein accumulation in atherosclerotic lesions. (C) 1999 by The American Society of Hematology.