© 1999 American Heart Association, Inc.
Original Contributions |
Cholesteryl Ester Hydroperoxide Lability Is a Key Feature of the Oxidative Susceptibility of Small, Dense LDL
From Institut National de la Santé et de la Recherche Médicale (INSERM) U321, Pavillon Benjamin Delessert, Hôpital de la Pitié (L.C., F.N., M.J.C.), Laboratoire de Biochimie "B," Hôpital de la Salpêtrière (S.L.), and Institut Fédératif de Recherche de Physiopathologie et de Génétique Cardiovasculaire, Centre Hospitalo-Universitaire de la Pitié-Salpêtrière (L.C., F.N., S.L., M.J.C.), Paris; and INSERM U347 (P.T., M.C.) and Laboratoire de Biochimie (P.T.), Hôpital de Bicêtre, Bicêtre, France.
Correspondence to Dr M.J. Chapman, INSERM U321, Hôpital de la Pitié, 75651 Paris Cédex 13, France.
Abstract—Abundant evidence has
been provided to substantiate the elevated
cardiovascular risk associated with small, dense, low
density lipoprotein (LDL) particles. The diminished resistance of dense
LDL to oxidative stress in both normolipidemic and
dyslipidemic subjects is established; nonetheless, the
molecular basis of this phenomenon remains indeterminate. We have
defined the primary molecular targets of lipid hydroperoxide formation
in light, intermediate, and dense subclasses of LDL after
copper-mediated oxidation and have compared the relative stabilities of
the hydroperoxide derivatives of phospholipids and cholesteryl esters
(CEs) as a function of the time course of oxidation. LDL subclasses
(LDL1 through LDL5) were isolated from normolipidemic plasma by
isopycnic density gradient ultracentrifugation, and
their content of polyunsaturated molecular species of
phosphatidylcholine (PC) and CE and of lipophilic antioxidants was
quantified by reverse-phase high-performance liquid
chromatography. The molar ratio of the particle content
of polyunsaturated CE and PC species containing linoleate or
arachidonate relative to 
-tocopherol or
ß-carotene did not differ significantly between LDL subspecies.
Nonetheless, dense LDL contained significantly less polyunsaturated CE
species (400 mol per particle) compared with LDL1 through LDL4 (range,
680 to 490 mol per particle). Although the formation of PC-derived
hydroperoxides did not vary significantly between LDL subspecies as a
function of the time course of copper-mediated oxidation, the abundance
of the C18:2 and C20:4 CE hydroperoxides was uniquely deficient in
dense LDL (23 and 0.6 mol per particle, respectively, in LDL5; 47 to 58
and 1.9 to 2.3 mol per particle, respectively, in other LDL subclasses)
at propagation half-time. When expressed as a lability ratio (mol
hydroperoxides formed relative to each 100 mol of substrate consumed)
at half-time, the oxidative lability of CE hydroperoxides in dense LDL
was significantly elevated (lability ratio <25:100) relative to that
in lighter, larger LDL particle subclasses (lability ratio >40:100)
throughout the oxidative time course. We conclude that the elevated
lability of CE hydroperoxides in dense LDL underlies the diminished
oxidative resistance of these particles. Moreover, this phenomenon
appears to result not only from the significantly elevated PC to free
cholesterol ratio (1.54:1) in dense LDL particles (1.15:1
to 1.25:1 for other LDL subclasses) but also from their unique
structural features, including a distinct apoB100 conformation, which
may facilitate covalent bond formation between oxidized CE and apoB100.
Key Words: LDL subclasses • reversed-phase high-performance liquid chromatography • lipophilic antioxidants • cholesteryl ester hydroperoxides • polyunsaturated fatty acids
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