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Published in Volume
101, Issue 12 (June 15,1998)
J. Clin. Invest.
101(12):
2702-2710 (1998).
doi:10.1172/JCI119891.
Copyright © 1998,
The American Society for Clinical Investigation
Research Article
Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice.
T Rajavashisth,
J H Qiao,
S Tripathi,
J Tripathi,
N Mishra,
M Hua,
X P Wang,
A Loussararian,
S Clinton,
P Libby and
A Lusis
Atherosclerosis Research Center, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. raja@cshs.org
Published June 15,
1998
Previous studies of osteopetrotic (op) mice lacking macrophage colony-stimulating factor (M-CSF) have revealed an inhibition of atherosclerosis development in the apolipoprotein E (apo E)-deficient model and in a diet-induced model. Using LDL receptor-deficient mice, we now show that atheroma development depends on M-CSF concentration, as not only did homozygous osteopetrotic (op/op) mice have dramatically reduced lesions (approximately 0.3% of control lesion size) but heterozygous (op/+) mice had lesions < 1% of controls. Mice heterozygous for the op mutation (op/+) had plasma levels of M-CSF about half those in controls (+/+). The finding that an approximately 2-fold reduction in M-CSF expression reduced lesion size approximately 100-fold suggests the requirement for a threshold level of M-CSF. The effect of M-CSF on atherosclerosis did not appear to be mediated either by changes in plasma lipoprotein levels or alterations in the number of circulating monocytes, since both op/op and op/+ mice exhibited higher levels of atherogenic lipoprotein particles and (op/+) mice showed a near normal number of circulating monocytes. LDL receptor-null littermates of genotypes from op/op, op/+, to +/+ showed monocyte differentials of approximately 4.5, 8, and 10%, respectively. Taken together, these results suggest that the effects of M-CSF on atherogenesis may not be mediated by expression of M-CSF systemically or by modulation of the number of circulating monocytes. These studies support the conclusion that M-CSF participates critically in fatty streak formation and progression to a complex fibrous lesion.
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