Molecular basis for the association of group IIA phospholipase A2 and decorin in human atherosclerotic lesions

Abstract

Group IIA secretory nonpancreatic phospholipase A2 (snpPLA2) is associated with collagen fibers in the extracellular matrix of human atherosclerotic plaques. Decorin, a small proteoglycan (PG) carrying chondroitin/dermatan sulfate glycosaminoglycans (GAGs), forms part of the collagen network in human arteries. To explore whether snpPLA2 may be associated with collagen fibers via interaction with decorin, we performed (1) immunohistochemistry to compare the relative in vivo localization of snpPLA2 and decorin in human atherosclerotic tissue and (2) in vitro experiments to study the interaction between snpPLA2 and decorin. In atherosclerotic lesions, decorin was detected within the snpPLA2-positive part of the intima close to the media. Electrophoretic mobility shift assay showed that snpPLA2 binds to decorin synthesized by human fibroblasts. Native and GAG-depleted decorin enhanced the association of snpPLA2 to collagen types I and VI in a solid-phase binding assay. Furthermore, snpPLA2 bound efficiently to a recombinant decorin core protein fragment B/E (Asp45- Lys359). This binding was competed with soluble decorin and inhibited at NaCl concentrations >150 mmol/L. The decorin core protein fragment B/E competed better than dermatan sulfate for binding of snpPLA2 to decorin-coated microtiter wells. The enzymatic activity of snpPLA2 increased 2- to 3-fold in the presence of decorin or GAG-depleted decorin. The results show that snpPLA2 binds preferentially to the decorin protein core rather than to the GAG chain and that this interaction enhances snpPLA2 activity. As a consequence, this active extracellular enzyme may contribute to the pathogenesis of atherosclerosis by modifying lipoproteins and releasing inflammatory lipid mediators at places of lipoprotein retention in the arterial wall.