An alternative mechanism for LDL macrophage uptake (and foam cell formation) that does not require prior formation of oxLDL is provided by mast cells. Mast cell degranulation produces neutral proteases, such as chymase, and granules. The released granules bind LDL and this LDL is also degraded and fused by the released proteases. In vivo evidence suggests that these non-oxidative modifications of LDL promote its phagocytosis by macrophages leading to foam cell formation in the human arterial intima (Kovanen, 1996). Although antioxidants certainly inhibit oxidative modifications to LDL they may also prevent atherosclerosis by inhibiting mast cell degranulation. It is known that mast cell degranulation and histamine release is stimulated by membrane lipid peroxidation and inhibited by antioxidants such as alpha-tocopherol (Masini et al., 1990). Mannaioni and Masini (1988) have provided an excellent review of the evidence linking histamine release with the generation of free radicals. Histamine, in turn, has many potential roles in atherogenesis. For example, histamine has been found to be an activator of human vascular smooth muscle growth by transcriptional stimulation of the c-fos proto-oncogene (Satoh et al., 1994). Mast cell derived TNF-alpha and TGF-beta 1 may also contribute to the proliferation of smooth muscle cells observed in atherosclerotic plaques.
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