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J Biol Chem, Vol. 273, Issue 44, 29127-29134, October 30, 1998

Sphingomyelinase Induces Aggregation and Fusion, but Phospholipase A₂ Only Aggregation, of Low Density Lipoprotein (LDL) Particles
TWO DISTINCT MECHANISMS LEADING TO INCREASED BINDING STRENGTH OF LDL TO HUMAN AORTIC PROTEOGLYCANS

Katariina Öörni, Jukka K. Hakala, Arto Annila, Mika Ala-Korpela, and Petri T. Kovanen

From the Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki and the  State Technical Research Centre of Finland, Chemical Technology, FIN-02044 Espoo, Finland

During atherogenesis, low density lipoprotein (LDL) particles bind to extracellular matrix proteoglycans in the arterial wall, become modified, and appear as aggregated and fused particles. Sphingomyelinase (SMase) and phospholipase A₂ (PLA₂) have been found in the arterial wall, and, moreover, lesional LDL shows signs of hydrolysis of both sphingomyelin and phosphatidylcholine. We have now studied the effects of these two lipolytic modifications on the aggregation and fusion of LDL particles by hydrolyzing the particles with Bacillus cereus SMase or bee venom PLA₂. In addition, the binding strengths of the modified LDL to human aortic proteoglycans (PG) were analyzed on an affinity column. We found that SMase induced aggregation and fusion of LDL, but PLA₂ induced only aggregation of the particles. In addition, the SMase-induced aggregation and fusion of LDL was promoted by pretreatment of LDL with PLA₂. Determination of the binding strengths of the hydrolyzed LDL revealed that mere lipolysis of LDL without aggregation or fusion, either by SMase or PLA₂, did not affect the binding of the particles to PG. Aggregation and fusion of lipolyzed LDL particles, however, increased their strength of binding to PG. Active lysine residues in apolipoprotein B-100 (apoB-100) appear to be involved in the binding of LDL to PG, and, in fact, quantitative ¹³C NMR analysis revealed that, in the fused LDL particles, the number of active lysine residues per apoB-100 moiety was increased. Moreover, aggregation and fusion of LDL increased the number of apoB-100 copies and, consequently, the number of active lysine residues per aggregate or fused particle. Our present findings therefore (i) show that treatment of LDL with SMase and PLA₂ generates modified LDL particles, which then bind to human aortic PG with increased strength, and (ii) suggest that SMase- and PLA₂-induced aggregation and fusion of LDL are potential mechanisms leading to focal retention of extracellular lipid in the arterial wall.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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