TRANSFERABLE LIPIDS IN OXIDIZED LOW-DENSITY-LIPOPROTEIN STIMULATE PLASMINOGEN-ACTIVATOR INHIBITOR-1 AND INHIBIT TISSUE-TYPE PLASMINOGEN-ACTIVATOR RELEASE FROM ENDOTHELIAL-CELLS
K. Kugiyama et al., TRANSFERABLE LIPIDS IN OXIDIZED LOW-DENSITY-LIPOPROTEIN STIMULATE PLASMINOGEN-ACTIVATOR INHIBITOR-1 AND INHIBIT TISSUE-TYPE PLASMINOGEN-ACTIVATOR RELEASE FROM ENDOTHELIAL-CELLS, Circulation research, 73(2), 1993, pp. 335-343
Decreased fibrinolytic activity has been reported in atherosclerotic c
ardiovascular diseases. To determine whether oxidized low-density lipo
protein (Ox-LDL), which accumulates in atherosclerotic arteries, modul
ates the endothelial fibrinolytic system, cultures of human umbilical
vein endothelial cells were incubated with low-density lipoproteins or
lipids, and levels of plasminogen activator inhibitor-1 (PAI-1) and t
issue-type plasminogen activator (t-PA) antigens in the conditioned me
dium were measured by enzyme-linked immunosorbent assay. Ox-LDL (30 mu
g protein/mL) and its extracted lipid (50 mug cholesterol/mL) stimulat
ed PAI-1 release by 42+/-3% and 29+/-3% of control cultures, respectiv
ely, whereas Ox-LDL and its lipid inhibited t-PA release by 42+/-4% an
d 53+/-3% of control cultures, respectively. Native LDL and its lipid
were inactive on their release. OX-LDL depleted of hydrophilic lipids,
which was prepared by the incubation with defatted albumin (an accept
or for hydrophilic lipids), lost both the stimulatory action on PAI-1
and the inhibitory action on t-PA. The extracted lipid from the incuba
ted albumin, which has been found to accept the hydrophilic lipids fro
m Ox-LDL, gained the stimulatory action on PAI-1 and the inhibitory ac
tion on t-PA. Ox-LDL depleted of lysophosphatidylcholine (LPC), which
was prepared by the incubation with phospholipase B, lost the stimulat
ory effect on PAI-1, whereas the inhibitory effect on t-PA remained pr
esent in the Ox-LDL depleted of LPC. The incubation with synthetic pal
mitoyl LPC (10 muM) stimulated PAI-I release by 85+/-7% of control. 25
-Hydroxycholesterol (50 muM) and 7-ketocholesterol (50 muM), both of w
hich were generated in Ox-LDL and were found to be transferable from O
x-LDL to defatted albumin by the analysis using gas chromatography-mas
s spectrometry, inhibited t-PA release by 26+/-3% and 31+/-3% of contr
ol cultures, respectively. The level of PAI activity in the conditione
d medium also increased after the incubation with Ox-LDL or LPC but no
t native LDL. The results indicate that Ox-LDL stimulates PAI-1 releas
e by the transferable hydrophilic lipid(s), especially LPC, whereas Ox
-LDL inhibits t-PA release by oxysterols or other transferable lipid(s
) from Ox-LDL to albumin rather than LPC. Lipid products in Ox-LDL may
impair endothelial fibrinolysis.