Rajavashisth T, Qiao J H, Tripathi S, Tripathi J, Mishra N, Hua M, Wang X P, Loussararian A, Clinton S, Libby P, Lusis A
Atherosclerosis Research Center, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
J Clin Invest. 1998 Jun 15;101(12):2702-10. doi: 10.1172/JCI119891.
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.
先前对缺乏巨噬细胞集落刺激因子（M-CSF）的骨硬化（op）小鼠的研究表明，在载脂蛋白E（apo E）缺陷模型和饮食诱导模型中，动脉粥样硬化的发展受到抑制。利用低密度脂蛋白受体缺陷小鼠，我们现在表明动脉粥样硬化的发展取决于M-CSF的浓度，因为不仅纯合骨硬化（op/op）小鼠的病变显著减少（约为对照病变大小的0.3%），而且杂合（op/+）小鼠的病变小于对照的1%。op突变杂合的小鼠（op/+）血浆中M-CSF水平约为对照（+/+）小鼠的一半。M-CSF表达降低约2倍会使病变大小减少约100倍，这一发现表明需要M-CSF达到阈值水平。M-CSF对动脉粥样硬化的影响似乎不是由血浆脂蛋白水平的变化或循环单核细胞数量的改变介导的，因为op/op和op/+小鼠都表现出更高水平的致动脉粥样硬化脂蛋白颗粒，并且（op/+）小鼠循环单核细胞数量接近正常。op/op、op/+至+/+基因型的低密度脂蛋白受体缺失同窝小鼠的单核细胞差异分别约为4.5%、8%和10%。综上所述，这些结果表明M-CSF对动脉粥样硬化发生的影响可能不是由全身M-CSF的表达或循环单核细胞数量的调节介导的。这些研究支持了M-CSF在脂肪条纹形成和发展为复杂纤维病变过程中起关键作用的结论。
