Membrane active lipids in remnant lipoproteins cause impairment of endothelium-dependent vasorelaxation.
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 alpha-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.
Doi
H
H
Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto, Japan.
Kugiyama
K
K
Ohgushi
M
M
Sugiyama
S
S
Matsumura
T
T
Ohta
Y
Y
Oka
H
H
Ogata
N
N
Hirata
A
A
Yamamoto
Y
Y
Yasue
H
H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D004907:Erythrocyte Deformability / Q000187:drug effects; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology*; D008297:Male; D008563:Membrane Lipids / Q000494:pharmacology*; D010545:Peroxides / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation
D000975:Antioxidants; D008074:Lipoproteins; D008563:Membrane Lipids; D010545:Peroxides; D010713:Phosphatidylcholines