Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice.
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.
Rajavashisth
T
T
Atherosclerosis Research Center, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. raja@cshs.org
Qiao
J H
JH
Tripathi
S
S
Tripathi
J
J
Mishra
N
N
Hua
M
M
Wang
X P
XP
Loussararian
A
A
Clinton
S
S
Libby
P
P
Lusis
A
A
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D006579:Heterozygote; D006720:Homozygote; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000473:pathology; D009154:Mutation; D010022:Osteopetrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*
D011973:Receptors, LDL; D016173:Macrophage Colony-Stimulating Factor