Osteopontin Deficiency Attenuates Atherosclerosis in Female Apolipoprotein E–Deficient Mice

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Abstract
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/6×129 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.

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