title: Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation.
abstract: The deposition of cholesterol ester within foam cells of the artery wall is fundamental to the pathogenesis of atherosclerosis. Modifications of low density lipoprotein (LDL), such as oxidation, are prerequisite events for the formation of foam cells. We demonstrate here that group X secretory phospholipase A2 (sPLA2-X) may be involved in this process. sPLA2-X was found to induce potent hydrolysis of phosphatidylcholine in LDL leading to the production of large amounts of unsaturated fatty acids and lysophosphatidylcholine (lyso-PC), which contrasted with little, if any, lipolytic modification of LDL by the classic types of group IB and IIA secretory PLA2s. Treatment with sPLA2-X caused an increase in the negative charge of LDL with little modification of apolipoprotein B (apoB) in contrast to the excessive aggregation and fragmentation of apoB in oxidized LDL. The sPLA2-X-modified LDL was efficiently incorporated into macrophages to induce the accumulation of cellular cholesterol ester and the formation of non-membrane-bound lipid droplets in the cytoplasm, whereas the extensive accumulation of multilayered structures was found in the cytoplasm in oxidized LDL-treated macrophages. Immunohistochemical analysis revealed marked expression of sPLA2-X in foam cell lesions in the arterial intima of high fat-fed apolipoprotein E-deficient mice. These findings suggest that modification of LDL by sPLA2-X in the arterial vessels is one of the mechanisms responsible for the generation of atherogenic lipoprotein particles as well as the production of various lipid mediators, including unsaturated fatty acids and lyso-PC.
authors.affiliation: Shionogi Research Laboratories, Shionogi and Co., Ltd., Sagisu 5-12-4, Fukushima-ku, Osaka 553-0002, Japan. kohji.hanasaki@shionogi.co.jp
authors.forename: Kohji
authors.initials: K
authors.lastname: Hanasaki
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yamada
authors.forename: Shigenori
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ishimoto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saiga
authors.forename: Takashi
authors.initials: T
authors.lastname: Ono
authors.forename: Minoru
authors.initials: M
authors.lastname: Ikeda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Notoya
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kamitani
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Arita
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism; D019327:Copper Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004587:Electrophoresis, Agar Gel; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005487:Foam Cells / Q000201:enzymology; D054509:Group X Phospholipases A2; D006801:Humans; D006868:Hydrolysis; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D010100:Oxygen / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D011994:Recombinant Proteins; D017392:Thiobarbituric Acid Reactive Substances; D016718:Arachidonic Acid; D010741:Phospholipases A; D054509:Group X Phospholipases A2; C516365:PLA2G10 protein, human; D054467:Phospholipases A2; C516366:Pla2g10 protein, mouse; D019327:Copper Sulfate; D010100:Oxygen