R. Eckey et al., MINIMAL OXIDATION AND STORAGE OF LOW-DENSITY LIPOPROTEINS RESULT IN AN INCREASED SUSCEPTIBILITY TO PHOSPHOLIPID HYDROLYSIS BY PHOSPHOLIPASEA(2), Atherosclerosis, 132(2), 1997, pp. 165-176
In vitro-studies have shown that phospholipid hydrolysis of low densit
y lipoproteins (LDL) by bee venom or porcine pancreatic phospholipase
A(2) (PLA(2)) leads to an increased uptake of these lipoproteins by ma
crophages transforming them into foam cells. Recently, a secretory pho
spholipase A(2), group II, was detected in human atherosclerotic plaqu
es. In order to investigate the role of this enzyme in the pathogenesi
s of atherosclerosis, a structurally identical human secretory PLA, wa
s purified from the medium of HepG2 cells stimulated with interleukin-
6 and tumor necrosis factor-alpha. The activity of the purified enzyme
towards the phospholipids of native and modified low density lipoprot
eins was compared with the activity towards Escherichia coli-membranes
and other phospholipid substrates. Compared to E. coli-membranes, nat
ive LDL proved to be a poor substrate for group II PLA(2). After mild
oxidation induced by copper ions or by 2,2-azobis(2-amidinopropane) (A
APH), the susceptibility of LDL to phospholipid hydrolysis was found t
o be increased by 25 and 23%, respectively, whereas extensive copper-m
ediated oxidation caused a decreased hydrolysis. Aging of LDL at 6 deg
rees C for weeks or at 37 degrees C for hours resulted in an increase
in PLA(2)-catalyzed phospholipid hydrolysis of up to 26-fold. LDL prot
ected from oxidation by probucol during aging showed a lesser increase
in susceptibility to phospholipid hydrolysis. Our results suggest tha
t PLA(2), group II, can increase the atherogenicity of LDL by its abil
ity to hydrolyze the phospholipids of these lipoproteins, especially a
fter modifications that are likely to occur in vivo. (C) 1997 Elsevier
Science Ireland Ltd.