© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Sphingomyelinase Converts Lipoproteins From Apolipoprotein E Knockout Mice Into Potent Inducers of Macrophage Foam Cell Formation
From the Departments of Medicine (S.M., Y.C., A.R.L., I.T.) and Anatomy and Cell Biology (I.T.), Columbia University, New York, NY.
Correspondence to Ira Tabas, MD, PhD, Department of Medicine, Columbia University, 630 West 168th St, New York, NY 10032. E-mail iat1{at}columbia.edu
Abstract—The
apoE knockout (E0) mouse is one of the most widely used animal models
of atherosclerosis, and there may be similarities to
chylomicron remnant–induced atherosclerosis in humans.
Although the lesions of these mice contain large numbers of cholesteryl
ester (CE)-laden macrophages (foam cells), E0 plasma
lipoproteins are relatively weak inducers of cholesterol
esterification in macrophages. Previous in vivo work has
suggested that arterial wall sphingomyelinase (SMase) may
promote atherogenesis in the E0 mouse, perhaps by inducing
subendothelial lipoprotein aggregation and subsequent
foam cell formation. The goal of the present study was to test the
hypothesis that the modification of E0 lipoproteins by SMase converts
these lipoproteins into potent inducers of macrophage foam cell
formation. When d<1.063 E0 lipoproteins were pretreated with SMase and
then incubated with E0 macrophages, cellular CE mass and
stimulation of the cholesterol esterification pathway were
increased 
5-fold compared with untreated lipoproteins. SMase-treated
E0 lipoproteins were more potent stimulators of cholesterol
esterification than either E0 lipoproteins in the presence of
lipoprotein lipases or oxidized E0 lipoproteins. The uptake and
degradation of SMase-treated E0 lipoproteins by macrophages
were saturable and specific and substantially inhibited by partial
proteolysis of cell-surface proteins. Uptake and degradation were
diminished by an anti-apoB antibody and by competition with human
Sf 100-400
hypertriglyceridemic VLDL, raising the
possibility that a receptor that recognizes apoB-48 might be involved.
In conclusion, SMase-modification of E0 lipoproteins, a process
previously shown to occur in lesions, may be an important mechanism for
foam cell formation in this widely studied model of
atherosclerosis. Moreover, the findings in this report
may provide important clues regarding the atherogenicity of chylomicron
remnants in humans.
Key Words: sphingomyelinase • lipoproteins • macrophages • foam cells • apolipoprotein E knockout mice
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