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J. Biol. Chem., Vol. 277, Issue 32, 29116-29124, August 9, 2002
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From the Shionogi Research Laboratories, Shionogi and Co., Ltd.,
Sagisu 5-12-4, Fukushima-ku, Osaka 553-0002, Japan
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.
Potent Modification of Low Density Lipoprotein by
Group X Secretory Phospholipase A2 Is Linked to Macrophage
Foam Cell Formation*
,
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 81-6-6455-2104;
Fax: 81-6-6458-0987; E-mail: kohji.hanasaki@shionogi.co.jp.
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