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Oxidized low density lipoprotein (oxLDL) induces apoptosis in human macrophages (Mphi), a significant feature in atherogenesis. We found that induction of apoptosis in Mphi by oxLDL, C2-ceramide, tumor necrosis factor alpha (TNF-alpha), and hydrogen peroxide (H2O2) was associated with enhanced expression of manganese superoxide dismutase (MnSOD) and p53. Treatment of cells with p53 or MnSOD antisense oligonucleotides prior to stimulation with oxLDL, C2-ceramide, TNF-alpha, or H2O2 caused an inhibition of the expression of the respective protein together with a marked reduction of apoptosis. Exposure to N-acetylcysteine before treatment with oxLDL, C2-ceramide, TNF-alpha, or H2O2 reversed a decrease in cellular glutathione concentrations as well as the enhanced production of p53 and MnSOD mRNA and protein. In apoptotic macrophages of human atherosclerotic plaques, colocalization of MnSOD and p53 immunoreactivity was found. These results indicate that in oxLDL-induced apoptosis, a concomitant induction of p53 and MnSOD is critical, and suggest that it is at least in part due to an enhancement of the sphingomyelin/ceramide pathway.

Durch Abanderung unserer fruheren Synthesevorschrift fur die Dithiapropellane werden die Oxathiapropellane 1–5 in praparativem Masstab hergestellt. Die Konfigurationen der aus 2–5 erhaltenen Monochloroxathiapropellandioxide 11–16 werden aufgeklart. Die Uberfuhrung von 11–16 in die entsprechenden Oxapropellene 17–19 ist von der Ringgrose des Carbocyclus abhangig. Das 3-Oxa[3.3.2]propell-9-en (17) entsteht nur in ca. 1 proz. Ausb. und ist damit das Oxapropellen mit dem kleinsten Carbocyclus, das nach diesem Syntheseweg hergestellt werden kann. Condensed Ring Systems, XII. On the Influence of the Carbocycle on the Reaction Course of the Ramberg-Backlund Reaction of Oxathiapropellanes By modification of our previous specifications for the syntheses of dithiapropellanes, oxathiapropellanes 1–5 are synthesized on a preparative scale. The configurations of monochloro-oxathiapropellane dioxides 11–16 obtained from 2–5 are elucidated. The transformation of 11–16 into the analogous oxapropellenes 17–19 is dependent on the ring size of the carbocycles. 3-Oxa[3.3.2]propell-9-ene (17) is obtained in about 1% yield only, and thus represents the oxapropellene with the smallest carbocycle preparable by this synthetic route.