Proteoglycans, group IIA phospholipase A2, and lipoproteins.Potential involvement in atherogenesis

Sammanfattning: Atherosclerosis is a multifactorial complex disease characterized by a focal accumulation of ApoB-100 containing lipoproteins, extracellular matrix (ECM), and cells in the arterial intima accompanied by an inflammatory reaction. In vivo and in vitro data supports the hypothesis that sulfated extracellular proteoglycans may be responsible for the selective retention of low density lipoproteins (LDL) in the arterial wall. Once retained in the intima, the lipoproteins are the targets for subsequent modifications that may lead to formation of large extracellular lipid aggregates and uptake by macrophages. Group IIA secretory non-pancreatic phospholipase A2 (snpPLA2) is a key enzyme involved in inflammatory processes with the specific function of hydrolyzing the sn-2 acyl group in phosphoglycerides and thereby liberating non-esterified fatty acids and lyso-phospholipids. Lipoproteins contain in their surface a substantial amount of phosphoglycerides and they may serve as physiological substrates for snpPLA2. Immunohistochemical studies have demonstrated abundant snpPLA2 associated with the ECM in human atherosclerotic lesions.The focus of this study was to investigate the interactions between snpPLA2 and proteoglycans synthesized by vascular cells as an attempt to characterize the molecular basis for the association of snpPLA2 with ECM components that are known to accumulate during atherosclerosis. In addition, the effects of sPLA2-modification of human plasma lipoproteins were analyzed. The results demonstrated that snpPLA2 binds differentially to proteoglycans and glycosaminoglycans and that these interactions modulate the enzyme activity. Specifically it was demonstrated that chondroitin-6-sulfate increased snpPLA2 activity, while heparin/heparan sulfate inhibited the enzyme. In addition, snpPLA2 bound efficiently to the core protein of decorin, a low molecular weight dermatan sulfate proteoglycan. Interestingly, this interaction appeared to mediate snpPLA2 association with collagen fibers, an observation supported by immunohistochemical analysis of human atherosclerotic tissue. Furthermore, sPLA2-modification of LDL in vitro lead to the formation of small, high density particles with increased affinity for proteoglycans. Hydrolysis of lipoproteins in human plasma by sPLA2 in vitro also generated smaller lipoprotein particles and large subfractions of LDL and high density lipoproteins were preferentially hydrolyzed by sPLA2.These results support the argument that the local snpPLA2-activity in the arterial wall may be modulated by the composition of the ECM with which snpPLA2 is associated. In addition, snpPLA2 may possibly be an important player involved in lipoprotein modification, and may by its action generate atherogenic lipoprotein particles (i.e. small dense LDL particles with increased affinity for proteoglycans). As a consequence, snpPLA2 may contribute to atherogenesis by generating pro-inflammatory lipid mediators and modifying lipoproteins in the arterial wall and in the circulation.