Oxidized phospholipids in oxidized low-density lipoprotein reduce the activity of tissue factor pathway inhibitor through association with its carboxy-terminal region.
Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits the initial reactions of blood coagulation. In this study, we explored the nature of active components that reduce the anticoagulant activity of TFPI in oxidized low-density lipoprotein (ox-LDL). The organic solvent-soluble fraction obtained from ox-LDL was fractionated by normal-phase HPLC. The binding profile of each fraction to TFPI showed a single peak eluting near purified oxidized phospholipid. To explore further the components in oxidized phospholipid that inhibit TFPI activity, we used oxidized phospholipids that mimic the biological activity of ox-LDL. The oxidation products of 1- and/or 2-oleoyl phosphatidylcholine or phosphatidylethanolamine were the most potent inhibitors of TFPI activity, whereas those of arachidonyl phosphatidylcholine possessed only a weak inhibitory effect on the TFPI activity. These oxidized phospholipids mainly associated with the C-terminal basic region of the TFPI molecule. The results indicate that oxidation products of delta-9 unsaturated phospholipids are candidate active components of ox-LDL that impair the function of TFPI through specific association with its C-terminal basic region.
Ohkura
Naoki
N
Department of Clinical Molecular Biology, Teikyo University, Tsukui, Kanagawa, 199-0195 Japan.
Hiraishi
Sayuri
S
Itabe
Hiroyuki
H
Hamuro
Tsutomu
T
Kamikubo
Yu-Ichi
Y
Takano
Tatsuya
T
Matsuda
Juzo
J
Horie
Shuichi
S
D000818:Animals; D002417:Cattle; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D008074:Lipoproteins; D008077:Lipoproteins, LDL; D010743:Phospholipids; C051928:lipoprotein-associated coagulation inhibitor; C099252:oxidized low density lipoprotein