| Co-Investigator(Kenkyū-buntansha) |
WATANABE Yoshio Kyoto university, 医学部, 助教授 (00031401)
YOSHIDA Haruyoshi Kyoto University (Higuchi,Masa), 医学部, 助教授 (80135574)
MATSUMORI Akira Kyoto University, 医学部, 助手 (70135573)
NARUMIYA Shuh Kyoto University, 医学部, 助教授 (70144350)
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| Budget Amount *help |
¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1987: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1986: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Research Abstract |
One of the initial characteristics of atherosclerosis shown in animal studies is the migration of circulating monocytes into the subendothelial space and their development into macrophages. Macrophages incorporate lipoproteins into the cell body and get converted into lipid-laden foam cells, which are characteristically found in the early stage of atheroma. However, macrophages have only a few number of classical low density lipoprotein (LDL) receptor, and thke up native LDL at a very low rate, which is insufficient to cause foam cell formation in vitro. Therefors, investigators have been attracted to other mechanism of incorporation and metabolism of lipoproteins in macrophages. These cells have been reported to efficiently incorporate <beta>-VLDL and VLDL from Watanabe heritable hyperlipidemic rabbits, an animal model for familial hypercholesterolemia via a specific receptor, the <beta>-VLDL receptor. Moreover, macrophages were also demonstrated to incorporate certain types of chemic
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ally modified LDL. This pathway was first shown for acetyl-LDL and the receptor is called the acetyl-LDL receptor. Although the discovery of this receptor appeared to explain the paradox of macrophages in ahterogenesis, a naturally occurring modified form of LDL has not yet been identified in the body. Recently oxidized LDL has been reported to be efficiently taken up by macrophages at least in part by may of acetyl-LDL receptor. Because lipid peroxidation has been suggested to be involved in atherogenesis by pathological of epidemiological investigation, oxidized LDL is considered as a candidate for an example of naturally occurring, modified LDL.
While foam cell formation of macrophages has been indicated to be one of the key events of atheroma formation, it has not been clarified yet whether it is only a process of accumulation of the lipid-laden cells or has some pathophysiological effects on the progression of atheroma. Macrophages release various biologically active substances when they are activated by phagocytic particles such as zymosan A or inflammatory stimuli such as lipopolysaccharidesl
Among those substances, the products derived from arachidonate metabolism have attracted increasing attention, since recent studies have indicated their close relation to atherogensis. However, little is known yet about arachidonate metabolism during the process of receptor-mediated incorporation of lipoproteins by macrophages and foam cell formation. Studies on this lind, therefore, would be of some value, in as much as it might give us a clue for determining the functional role of the foram cells as to whether they act as a promotor for atheromatous formation.
In this study, we incubated mouse peritoneal macrophages with lipoproteins and examined production of arachidonate metabolites with gas chromatography-mass spectrometry and redioimmunoassay. We report that oxidized LDL stimulates arachidonate metabolism in macrophages during its incorporation into the cells. Less
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