Niemann-Pick C heterozygosity confers resistance to lesional @entity39 and macrophage apoptosis in @entity19 XXXX .

@entity6970 @entity137 @entity39 @entity19 @entity1977 @entity30385 @entity1442 @entity1344 @entity731 @entity165
Macrophage death in advanced @entity731 leads to lesional @entity39 and likely promotes @entity1344 , a precursor of acute vascular events. Macrophages in @entity1442 accumulate large amounts of unesterified @entity165 , which is a potent inducer of macrophage apoptosis. We have shown recently that induction of apoptosis in cultured macrophages requires @entity165 trafficking to the endoplasmic reticulum (ER). Moreover, macrophages from @entity19 with a heterozygous mutation in the @entity165 -trafficking protein @entity30385 have a selective defect in @entity165 trafficking to the ER and are protected from @entity165 -induced apoptosis. The goal of the present study was to test the importance of intracellular @entity165 trafficking in atherosclerotic lesional macrophage death by comparing lesion morphology in @entity30385 +/+; @entity6970 -/- and @entity30385 +/-; @entity6970 -/- @entity19 . Although @entity1442 in @entity30385 +/+; @entity6970 -/- @entity19 had extensive acellular areas that were rich in unesterified @entity165 and macrophage debris, the lesions of @entity30385 +/-; @entity6970 -/- @entity19 were substantially more cellular and less @entity39 . Moreover, compared with @entity30385 +/-; @entity6970 -/- lesions, @entity30385 +/+; @entity6970 -/- lesions had a greater number of large, TUNEL (terminal deoxynucleotidyltransferase-mediated @entity1977 nick end labeling)-positive areas surrounding @entity39 areas, indicative of macrophage apoptosis. These differences were observed despite similar total lesion area and similar plasma lipid levels in the two groups of @entity19 . These data provide in vivo evidence that intact intracellular @entity165 trafficking is important for macrophage apoptosis in advanced @entity731 and that the ER-based model of @entity165 -induced @entity137 is physiologically relevant. Moreover, by showing that lesional @entity39 can be diminished by a subtle defect in intracellular trafficking, these findings suggest therapeutic strategies to stabilize atherosclerotic plaques.
