Circulating LDL that enters the blood vessel wall is the main source of cholesterol that accumulates within vessel wall atherosclerotic plaques, the cause of most heart attacks and strokes. Much of the deposited cholesterol accumulates within plaque macrophages converting these macrophages into cholestrol-rich foamy looking cells. It is generally believed that only LDL modified by oxidation, but not native LDL, can cause cholesterol accumulation in macrophages. However, most LDL within atherosclerotic plaques is not oxidized, and oxidized LDL is a poor inducer of macrophage cholesterol accumulation. In the present research project, we have investigated how modification of macrophages rather than modification of LDL affects macrophage metabolism of native LDL. We show that macrophage foam cell formation can occur with native LDL when macrophages are activated through protein kinase C signaling pathways. Activation of cultured human monocyte-derived macrophages stimulates their uptake and degradation of native LDL. LDL uptake does not depend on macrophage oxidation of LDL or increased macrophage binding of LDL. Also, uptake does not depend on LDL apoB protein because removal of this protein does not affect LDL uptake. Rather, activated macrophages show greatly stimulated uptake of LDL as part of the bulk-phase fluid that these activated macrophages take up from stimulated fluid-phase endocytosis. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques. This novel mechanism of macrophage cholesterol accumulation shows that modification of LDL is not necessary for foam cell formation to occur. In addition, the findings direct attention to macrophage fluid-phase endocytosis as a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis.
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