Molecular basis for the association of group IIA phospholipase A(2) and decorin in human atherosclerotic lesions

Group IIA secretory nonpancreatic phospholipase A(2) (snpPLA(2)) is associa ted with collagen fibers in the extracellular matrix of human atherosclerot ic plaques. Decorin, a small proteoglycan (PG) carrying chondroitin/ dermat an sulfate glycosaminoglycans (GAGs), forms part of the collagen network in human arteries. To explore whether snpPLA(2) may be associated with collag en fibers via interaction with decorin, we performed (1) immunohistochemist ry to compare the relative in vivo localization of snpPLA(2) and decorin in human atherosclerotic tissue and (2) in vitro experiments to study the int eraction between snpPLA(2) and decorin. In atherosclerotic lesions, decorin was detected within the snpPLA(2)-positive part of the intima close to the media. Electrophoretic mobility shift assay showed that snpPLA(2) binds to decorin synthesized by human fibroblasts, Native and GAG-depleted decorin enhanced the association of snpPLA(2) to collagen types I and VI in a solid -phase binding assay. Furthermore, snpPLA(2) bound efficiently to a recombi nant decorin core protein fragment B/E (Asp45-Lys359). This binding was com peted with soluble decorin and inhibited at NaCl concentrations >150 mmol/L , The decorin core protein fragment B/E competed better than dermatan sulfa te for binding of snpPLA(2) to decorin-coated microtiter wells. The enzymat ic activity of snpPLA(2) increased 2- to 3-fold in the presence of decorin or GAG-depleted decorin. The results show that snpPLA(2) binds preferential ly to the decorin protein core rather than to the GAG chain and that this i nteraction enhances snpPLA(2) activity. As a consequence, this active extra cellular enzyme may contribute to the pathogenesis of atherosclerosis by mo difying lipoproteins and releasing inflammatory lipid mediators at places o f lipoprotein retention in the arterial wall.