Phospholipase A(2) modification of low density lipoproteins forms small high density particles with increased affinity for proteoglycans and glycosaminoglycans

The presence of a lipoprotein profile with abundance of small, dense low de nsity lipoproteins (LDL), low levels of high density lipoproteins (HDL), an d elevated levels of triglyceride-rich very low density lipoproteins is ass ociated with an increased risk for coronary heart disease. The atherogenici ty of small, dense LDL is believed to be one of the main reasons for this a ssociation. This particle contains less phospholipids (PL) and unesterified cholesterol than large LDL, and the apoB-100 appears to occupy a more exte nsive area at its surface. Although there are experiments that suggest a me tabolic pathway leading to the overproduction of small, dense LDL, no clear molecular model exists to explain its association with atherogenesis. A cu rrent hypothesis is that small, dense LDL, because of its higher affinity f or proteoglycans, is entrapped in the intima extracellular matrix and is mo re susceptible to oxidative modifications than large LDL. Here we describe how a specific reduction of approximately 50% of the PL of a normal buoyant LDL by immobilized phospholipase A(2) (PLA(2)) (EC 3.1.1.4) produces small er and denser particles without inducing significant lipoprotein aggregatio n (<5%), These smaller LDL particles display a higher tendency to form nons oluble complexes with proteoglycans and glycosaminoglycans than the parent LDL, Binding parameters of LDL and glycosaminoglycans and proteoglycans pro duced by human arterial smooth muscle cells were measured at near to physio logical conditions. The PLA(2)-modified LDL has about 2 times higher affini ty for the sulfated polysaccharides than control LDL, In addition, incubati on of human plasma in the presence of PLA(2) generated smaller LDL and HDL particles compared with the control plasma incubated without PLA(2). These in vitro results indicate that the reduction of surface PL characteristic o f small, dense LDL subfractions, besides contributing to its small size and density, may enhance its tendency to be retained by proteoglycans.