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 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 snpPLA(2) may be associated with collagen fibers via interaction with decorin, we performed (1) immunohistochemistry to compare the relative in vivo localization of snpPLA(2) and decorin in human atherosclerotic tissue and (2) in vitro experiments to study the interaction 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 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 snpPLA(2) to decorin-coated microtiter wells. The enzymatic 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 preferentially to the decorin protein core rather than to the GAG chain and that this interaction enhances snpPLA(2) 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.
Sartipy
P
P
Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden. peter.sartipy@wlab.wall.gu.se
Johansen
B
B
Gâsvik
K
K
Hurt-Camejo
E
E
D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D058575:Decorin; D016326:Extracellular Matrix Proteins; D054501:Group II Phospholipases A2; D006801:Humans; D007150:Immunohistochemistry; D010741:Phospholipases A / Q000378:metabolism*; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D012016:Reference Values; D014018:Tissue Distribution
C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D003094:Collagen; D010741:Phospholipases A; D054501:Group II Phospholipases A2