INCREASED ACTIVITY OF PLATELET-ACTIVATING-FACTOR ACETYLHYDROLASE IN LOW-DENSITY-LIPOPROTEIN SUBFRACTIONS INDUCES ENHANCED LYSOPHOSPHATIDYLCHOLINE PRODUCTION DURING OXIDATION IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
Sap. Karabina et al., INCREASED ACTIVITY OF PLATELET-ACTIVATING-FACTOR ACETYLHYDROLASE IN LOW-DENSITY-LIPOPROTEIN SUBFRACTIONS INDUCES ENHANCED LYSOPHOSPHATIDYLCHOLINE PRODUCTION DURING OXIDATION IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA, European journal of clinical investigation, 27(7), 1997, pp. 595-602
Citations number
49
Categorie Soggetti
Medicine, Research & Experimental","Medicine, General & Internal
Patients with heterozygous familial hypercholesterolaemia (FH) have el
evated plasma concentrations of low-density lipoprotein (LDL) and deve
lop premature atherosclerosis. There is increasing evidence that oxida
tive modification of LDL is important for the pathogenesis of atherosc
lerosis, and the LDL-associated platelet-activating factor acetylhydro
lase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing
the oxidized phospholipids of phosphatidylcholine (PC) and producing
lysophosphatidylcholine (lyso-PC). We measured the total serum and hig
h-density lipoprotein (HDL) levels of PAF-AH activity and studied the
distribution of PAF-AH activity among three LDL subfractions isolated
by gradient ultracentrifugation in 15 patients with heterozygous FH an
d 13 normolipidaemic control subjects. We also determined the lyse-PC
production in each LDL subfraction during Cu2+-induced oxidation in vi
tro. The total serum PAF-AH activity in heterozygous FH patients was s
ignificantly higher than in control subjects, whereas the HDL-associat
ed PAF-AH activity, expressed as a percentage of total serum PAF-AH ac
tivity, was significantly lower in the FH patients than in control sub
jects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subf
ractions, the PAF-AH activity in both normolipidaemic control subjects
and FH patients, expressed as nmol mg(-1) protein min(-1), was signif
icantly higher in the LDL3 subfraction (3.31 +/- 4.8 and 53.4 +/- 11.5
respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respec
tively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/
- 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons).
Additionally, the enzyme activity in each LDL subfraction of the hete
rozygous FH patients was significantly higher than in control subjects
(P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No di
fference was observed in the susceptibility to oxidation of each LDL s
ubfraction among the heterozygous FH patients and the normolipidaemic
control subjects. During oxidation, the PAF-AH activity decreased, whe
reas the lyse-PC levels significantly increased in all subfractions of
both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfra
ction of the FH patients 3 h after the onset of the oxidation was sign
ificantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/-
0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0
.03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.0
6, respectively, for LDL3 (P < 0.02)]. Our results show that heterozyg
ous FH patients exhibit higher PAF-AH activity than control subjects i
n all LDL subfractions, resulting in higher lyso-PC production during
oxidation, which confers on these subfractions higher biological poten
cy. This phenomenon, in combination with the diminished anti-atherogen
ic and antioxidant capability of HDL in these patients due to the rela
tively low HDL-cholesterol levels compared with LDL-cholesterol levels
and, consequently, the relatively low HDL-associated PAF-AH activity,
could contribute to the higher atherogenicity and incidence of corona
ry artery disease observed in FH patients.