Sphingomyelinase converts lipoproteins from apolipoprotein E knockout miceinto potent inducers of macrophage foam cell formation

The apoE knockout (EO) mouse is one of the most widely used animal models o f atherosclerosis, and there may be similarities to chylomicron remnant-ind uced atherosclerosis in humans. Although the lesions of these mice contain large numbers of cholesteryl eater (CE)-laden macrophages (foam cells), EO plasma lipoproteins are relatively weak inducers of cholesterol esterificat ion in macrophages. Previous in vivo work has suggested that arterial wall sphingomyelinase (SMase) may promote atherogenesis in the EO mouse, perhaps by inducing subendothelial lipoprotein aggregation and subsequent foam cel l formation. The goal of the present study was to test the hypothesis that the modification of EO lipoproteins by SMase converts these lipoproteins in to potent inducers of macrophage foam cell formation. When d<1.063 EO lipop roteins were pretreated with SMase and then incubated with EO macrophages, cellular CE mass and stimulation of the cholesterol esterification pathway were increased <approximate to>5-fold compared with untreated lipoproteins. SMase-treated EO lipoproteins were more potent stimulators of cholesterol esterification than either EO lipoproteins in the presence of lipoprotein l ipases or oxidized EO lipoproteins. The uptake and degradation of SMase-tre ated EO lipoproteins by macrophages were saturable and specific and substan tially inhibited by partial proteolysis of cell-surface proteins. Uptake an d degradation were diminished by an anti-apoB antibody and by competition w ith human S-f 100-400 hypertriglyceridemic VLDL, raising the possibility th at a receptor that recognizes apoB-48 might be involved. In conclusion, SMa se-modification of EO lipoproteins, a process previously shown to occur in lesions, may be an important mechanism for foam cell formation in this wide ly studied model of atherosclerosis. Moreover, the findings in this report may provide important clues regarding the atherogenicity of chylomicron rem nants in humans.