(Circulation. 1999;99:1740-1746.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Intraperitoneal Administration of Anti–c-fms Monoclonal Antibody Prevents Initial Events of Atherogenesis but Does Not Reduce the Size of Advanced Lesions in Apolipoprotein E–Deficient Mice
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10 to 13, 1996, and published in abstract form in Circulation (1996; 94[suppl I]:I-633).
From the Departments of Geriatric Medicine (T.M., M.Y., H.K., T.I., H.Y., H.S., T.K.) and Molecular Genetics (H.K., S.N., S.-I.N.), Graduate School of Medicine, Kyoto University, Japan.
Correspondence to Masayuki Yokode, MD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail yokode{at}kuhp.kyoto-u.ac.jp
Background—Atherosclerosis results from complex inflammatory-fibroproliferative responses. To elucidate the central role of macrophage and macrophage-colony stimulating factor (M-CSF) during atherogenesis, we used a new strategy to administer to adult apolipoprotein E (apoE)-deficient mice a monoclonal antibody (AFS98) raised against c-fms, the receptor of M-CSF.
Methods and Results—When 6-week-old apoE-deficient mice were fed a high-fat diet and injected with 2 mg of AFS98 intraperitoneally on alternate days for 6 weeks, accumulation of macrophage-derived foam cells in the aortic root was suppressed by 70% compared with that in controls. This preventive effect was associated with neither remarkable decrease of the number of circulating monocytes nor systemic growth retardation. In contrast, when apoE-deficient mice that had been fed a high-fat diet from 6 weeks of age were given AFS98 from 12 to 18 weeks of age, a minimal protective effect on lesion size was observed.
Conclusions—These results suggest that (1) macrophage and M-CSF/c-fms play an essential role in the arterial wall during development of the fatty streak lesion and (2) blockade of the M-CSF/c-fms pathway could act as protection from at least early atherogenesis but could have a less preventive effect on maintenance of the advanced lesions.
Key Words: antibodies • atherosclerosis • leukocytes
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