Published online before print May 1, 2003, doi: 10.1161/01.ATV.0000074878.29805.D0
© 2003 American Heart Association, Inc.
Vascular Biology |
Osteopontin Deficiency Attenuates Atherosclerosis in Female Apolipoprotein E–Deficient Mice
From the Division of Molecular Immunology (Y.M., M.I., J.M., C.K., S.K., T.U.), Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Cardiovascular Medicine (Y.M., H.O., N.J., T.S., M.A., T.S., A.K.), Hokkaido University Graduate School of Medicine, Sapporo, Japan; and Departments of Genetics (S.R.R.) and Cell Biology and Neuroscience (D.D.), Rutgers University, Piscataway, NJ.
Correspondence to Toshimitsu Uede, MD, Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan. E-mail toshi{at}imm.hokudai.ac.jp
Objective— Osteopontin (OPN), a noncollagenous adhesive protein, is implicated in atherosclerosis, in which macrophages within atherosclerotic plaques express OPN. However, it is not known whether the elevated OPN expression is a cause or result of atherosclerosis.
Methods and Results— We generated mice that lacked OPN and crossed them with apolipoprotein (apo) E–deficient mice and analyzed these mice with a mixed C57BL/6x129 background after 36 weeks on a normal chow diet. In female mice, OP+/-E-/- and OP-/-E-/- mice had significantly smaller atherosclerotic and inflammatory lesions compared with OP+/+E-/- mice, and that was reflected by smaller area of MOMA-2–positive staining. In male mice, however, there was no significant difference in the atherosclerosis lesion areas among 3 genotypes. In both OP-/-E-/- and OP+/+E-/- mice, typical atherosclerotic lesions were detected, which include necrotic core, foamy cell collections, and cholesterol clefts. However, we found that vascular mineral-deposited areas in 60-week-old male OP-/-E-/- mice were significantly increased compared with those in OP+/+E-/- male mice.
Conclusions— These results suggest that OPN plays a promoting effect in atherosclerosis and inhibitory effect in vascular calcification. The suppression of OPN expression in females should be considered a therapeutic possibility in atherosclerosis.
Key Words: osteopontin • atherosclerosis • macrophage • calcification • lipid metabolism
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