© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Membrane Active Lipids in Remnant Lipoproteins Cause Impairment of Endothelium-Dependent Vasorelaxation
From the Departments of Cardiovascular Medicine (H.D., K.K., M.O., S.S., T.M., Y.O., H.O., N.O., H.Y.) and Ophthalmology (A.H.), Kumamoto University School of Medicine, Kumamoto; and the Research Center for Advanced Science and Technology (Y.Y.), University of Tokyo, Japan.
Correspondence to Kiyotaka Kugiyama, MD, Division of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City, Kumamoto 860-8556, Japan. E-mail kiyo{at}gpo.kumamoto-u.ac.jp
Abstract—We have recently
found that remnant lipoproteins (RLPs) and their lipid fractions impair
endothelium-dependent vasorelaxation (EDR). This study
was aimed at clarifying mechanisms responsible for RLP-induced
endothelial dysfunction in isolated rabbit aortas. RLPs
were isolated from plasma in hyperlipidemic subjects by
use of the immunoaffinity gel mixture of anti-ApoA1 and anti-ApoB100
monoclonal antibodies and ultracentrifugation. Organ
chamber experiments showed that EDR impairment was restored by addition
of reduced glutathione (GSH) or N-acetylcysteine,
antioxidants, into the incubation buffer containing isolated rabbit
aortas and RLPs (0.75 mg of triglyceride/mL). Furthermore,
the incubation of isolated human red blood cells (RBCs) with RLP and
its lipids converted the normal shape of RBCs to echinocytes, but
coincubation with antioxidants suppressed the RLP-induced RBC
transformation, suggesting that they exerted oxidative damage on RBC
surface membranes. Studies with HPLC and the postcolumn
chemiluminescence method showed that RLPs contain a substantial amount
of phosphatidylcholine hydroperoxides. Peroxidized phosphatidylcholine
also impaired EDR and had echinocytogenic action, both of which were
suppressed by N-acetylcysteine. RLPs isolated from the
plasma of patients under treatment with 
-tocopherol, an
antioxidant, had a lower level of phosphatidylcholine hydroperoxides
(15% of the amount in nontreated patients), which was associated with
a lack of the inhibitory action on EDR and with lesser
effect on RBC transformation. Oxidative damage caused by lipid
components in RLPs, especially peroxidized phospholipids, deteriorates
cell surface membrane and may be at least partly responsible for
RLP-induced impairment of EDR.
Key Words: endothelium • lipoproteins • antioxidants • endothelial-derived factors • hyperlipoproteinemia
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