Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice

J Clin Invest. 1998 Jun 15;101(12):2702-10. doi: 10.1172/JCI119891.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arteriosclerosis / genetics*
  • Arteriosclerosis / metabolism
  • Arteriosclerosis / pathology
  • Cell Differentiation
  • Heterozygote
  • Homozygote
  • Macrophage Colony-Stimulating Factor / deficiency
  • Macrophage Colony-Stimulating Factor / genetics*
  • Macrophages / pathology
  • Mice
  • Monocytes / pathology
  • Mutation
  • Osteopetrosis / genetics*
  • Osteopetrosis / metabolism
  • Osteopetrosis / pathology
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics*

Substances

  • Receptors, LDL
  • Macrophage Colony-Stimulating Factor